Substituted alkylamine derivatives and methods of use

ABSTRACT

Selected heterocyclic compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like.

This application is a continuation of U.S. patent application Ser. No.11/234,713, filed Sep. 23, 2005 which claims benefit of 10/046,681 filedJan. 10, 2002 which claims benefit of U.S. Provisional Application Nos.60/261,339, filed Jan. 12, 2001, and 60/323,764 filed Sep. 19, 2001which are hereby incorporated by reference.

FIELD OF THE INVENTION

This invention is in the field of pharmaceutical agents and specificallyrelates to compounds, compositions, uses and methods for treating cancerand angiogenesis-related disorders.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processes,maintaining control over cellular function. A partial list of suchkinases includes ab1, Atk, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src,CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1,CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2,FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak,KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK,Yes, and Zap70. Inhibition of such kinases has become an importanttherapeutic target.

Certain diseases are known to be associated with deregulatedangiogenesis, for example ocular neovascularization, such asretinopathies (including diabetic retinopathy), age-related maculardegeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis,inflammatory disease, such as a rheumatoid or rheumatic inflammatorydisease, especially arthritis (including rheumatoid arthritis), or otherchronic inflammatory disorders, such as chronic asthma, arterial orpost-transplantational atherosclerosis, endometriosis, and neoplasticdiseases, for example so-called solid tumors and liquid tumors (such asleukemias).

At the center of the network regulating the growth and differentiationof the vascular system and its components, both during embryonicdevelopment and normal growth, and in a wide number of pathologicalanomalies and diseases, lies the angiogenic factor known as VascularEndothelial Growth Factor” (VEGF; originally termed ‘VascularPermeability Factor”, VPF), along with its cellular receptors (see G.Breier et al., Trends in Cell Biology, 6, 454-6 (1996)).

VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein related to“Platelet-Derived Growth Factor” (PDGF); it is produced by normal celllines and tumor cell lines; is an endothelial cell-specific mitogen;shows angiogenic activity in in vivo test systems (e.g. rabbit cornea);is chemotactic for endothelial cells and monocytes; and inducesplasminogen activators in endothelial cells, which are involved in theproteolytic degradation of extracellular matrix during the formation ofcapillaries. A number of isoforms of VEGF are known, which showcomparable biological activity, but differ in the type of cells thatsecrete them and in their heparin-binding capacity. In addition, thereare other members of the VEGF family, such as “Placenta Growth Factor”(PlGF) and VEGF-C.

VEGF receptors (VEGFR) are transmembranous receptor tyrosine kinases.They are characterized by an extracellular domain with sevenimmunoglobulin-like domains and an intracellular tyrosine kinase domain.Various types of VEGF receptor are known, e.g. VEGFR-1 (also known asflt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

A large number of human tumors, especially gliomas and carcinomas,express high levels of VEGF and its receptors. This has led to thehypothesis that the VEGF released by tumor cells stimulates the growthof blood capillaries and the proliferation of tumor endothelium in aparacrine manner and through the improved blood supply, accelerate tumorgrowth. Increased VEGF expression could explain the occurrence ofcerebral edema in patients with glioma. Direct evidence of the role ofVEGF as a tumor angiogenesis factor in vivo is shown in studies in whichVEGF expression or VEGF activity was inhibited. This was achieved withanti-VEGF antibodies, with dominant-negative VEGFR-2 mutants whichinhibited signal transduction, and with antisense-VEGF RNA techniques.All approaches led to a reduction in the growth of glioma cell lines orother tumor cell lines in vivo as a result of inhibited tumorangiogenesis.

Angiogenesis is regarded as an absolute prerequisite for tumors whichgrow beyond a diameter of about 1-2 mm; up to this limit, oxygen andnutrients may be supplied to the tumor cells by diffusion. Every tumor,regardless of its origin and its cause, is thus dependent onangiogenesis for its growth after it has reached a certain size.

Three principal mechanisms play an important part in the activity ofangiogenesis inhibitors against tumors: 1) Inhibition of the growth ofvessels, especially capillaries, into avascular resting tumors, with theresult that there is no net tumor growth owing to the balance that isachieved between cell death and proliferation; 2) Prevention of themigration of tumor cells owing to the absence of blood flow to and fromtumors; and 3) Inhibition of endothelial cell proliferation, thusavoiding the paracrine growth-stimulating effect exerted on thesurrounding tissue by the endothelial cells which normally line thevessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11,77-114 (2001).

VEGF's are unique in that they are the only angiogenic growth factorsknown to contribute to vascular hyperpermeability and the formation ofedema. Indeed, vascular hyperpermeability and edema that is associatedwith the expression or administration of many other growth factorsappears to be mediated via VEGF production.

Inflammatory cytokines stimulate VEGF production. Hypoxia results in amarked upregulation of VEGF in numerous tissues, hence situationsinvolving infarct, occlusion, ischemia, anemia, or circulatoryimpairment typically invoke VEGF/VPF-mediated responses. Vascularhyperpermeability, associated edema, altered transendothelial exchangeand macromolecular extravasation, which is often accompanied bydiapedesis, can result in excessive matrix deposition, aberrant stromalproliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability cansignificantly contribute to disorders with these etiologic features. Assuch, regulators of angiogenesis have become an important therapeutictarget.

Schipper U.S. Pat. No. 3,226,394, issued Dec. 28, 1965, describesanthranilamides as CNS depressants. Japanese patent JP2000256358describes pyrazole derivatives that block the calcium release-activatedcalcium channel. EP application 9475000, published 6 Oct. 1999,describes compounds as PGE₂ antagonists. PCT publication WO96/41795,published 27 Dec. 1996, describes benzamides as vasopressin antagonists.WO01/29009 describes aminopyridines as KDR inhibitors. WO01/30745describes anthranilic acids as CGMP phosphodiesterase inhibitors.WO00/02851, published 20 Jan. 2000 describes arylsulfonylamnoaryl amidesas guanylate cyclase activators. WO98/45268 describes nicotinamidederivatives as PDE4 inhibitors. WO98/24771 describes benzamides asvasopressin antagonists.

U.S. Pat. No. 5,532,358, issued Jul. 2, 1996, describes the preparationof2-(cyclopropylamino)-N-(2-methoxy-4-methyl-3-pyridinyl)-3-pyridinecarboxamideas an intermediate for HIV inhibitors. Triazine-substituted amines aredescribed for their aggregating ability (J. Amer. Chem. Soc., 115,905-16 (1993). Substituted imidazolines were tested for theirantidepressant activity in Ind. J. Het. Chem., 2, 129-32 (1992).N-(4-Pyridyl)anthranilic amides were described in Chem. Abstr. 97:109837(1981). PCT publication WO99/32477, published 1 Jul. 1999, describesanthranilamides as anti-coagulants. U.S. Pat. No. 6,140,351 describesanthranilamides as anti-coagulants. PCT publication WO99/62885,published 9 Dec. 1999, describes 1-(4-aminophenyl)pyrazoles asantiinflammatories. PCT publication WO00/39111, published 6 Jul. 2000,describes amides as factor Xa inhibitors. PCT publication WO00/39117,published 6 Jul. 2000, describes heteroaromatic amides as factor Xainhibitors. PCT publication WO00/27819, published 18 May 2000, describesanthranilic acid amides as VEGF inhibitors. PCT publication WO00/27820published 18 May 2000, describes N-aryl anthranilic acid amides as VEGFinhibitors. 7-Chloroquinolinylamines are described in FR2168227 asantiinflammatories. WO01/55114, published 2 Aug. 2001, describesnicotinamides for the treatment of cancer. WO01/55115, published 2 Aug.2001, describes nicotinamides as inducers of apoptosis. WO01/85715,published 15 Nov. 2001, describes substituted pyridines and pyrimidinesas anti-angiogenesis agents. PCT publication WO01/85691 published 15Nov. 2001, describes anthranilic amides as VEGF inhibitors. PCTpublication WO01/85671 published 15 Nov. 2001, describes anthranylamides as VEGF inhibitors. PCT publication WO01/81311 published 1 Nov.2001, describes anthranilic amides as VEGF inhibitors. However,compounds of the current invention have not been described as inhibitorsof angiogenesis such as for the treatment of cancer.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating cancer and angiogenesis isdefined by Formula I

-   wherein each of A¹ and A² is independently C, CH or N;-   wherein ring A is selected from    -   a) 5- or 6-membered partially saturated heterocyclyl,        -   preferably dihydropyran, dihydrothienyl, dihydrofuryl,            oxo-dihydrofuryl, pyrrolinyl, dihydrothiazolyl,            dihydro-oxazolyl, dihydro-isothiazolyl, dihydro-isoxazolyl,            imidazolinyl and pyrazolinyl,    -   b) 5- or 6-membered heteroaryl,        -   preferably            -   I) 5-membered heteroaryl selected from thienyl, furanyl,                pyrrolyl, triazolyl, oxazolyl, imidazolyl, pyrazolyl,                isoxazolyl, triazolyl and isothiazolyl,                -   even more preferably 5-membered heteroaryl selected                    from

-   -   -   -   -   specifically

-   -   -   -   -    and

            -   II) preferably 6-membered heteroaryl selected from                pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and                triazinyl,                -   even more preferably 6-membered heteroaryl selected                    from

-   -   -   -   -   more specifically

-   -   c) 9-, 10- or 11-membered fused partially saturated heterocyclyl        -   preferably tetrahydroquinolinyl,    -   d) 9- or 10-membered fused heteroaryl,        -   preferably            -   i) fused 9-membered fused heteroaryl selected from                benzothienyl, benzothiazolyl, indolyl, benzimidazolyl,                benzoxazolyl, benzofuryl, indazolyl and isoindolyl, and            -   ii) fused 10-membered heteroaryl selected from quinolyl,                isoquinolyl, naphthpyridinyl, quinoxalinyl and                quinazolinyl,    -   e) naphthyl, and    -   f) 4-, 5- or 6-membered cycloalkenyl,        -   preferably 5-membered cycloalkenyl,            -   more preferably cyclopentadienyl or cyclopentenyl;

-   wherein X is selected from

-   -   preferably X is selected from

-   -   -   more preferably X is

-   wherein Z is oxygen or sulfur;-   wherein Y is selected from

-   -   preferably Y is selected from

-   -   -   more preferably Y is selected from

-   -   -   -   even more preferably Y is —NH—CH₂—;

-   wherein R^(a) and R^(b) are independently selected from H, halo,    cyano and C₁₋₄-alkyl substituted with R², or wherein R^(a) and    -   R^(b) together form C₃-C₄ cycloalkyl,        -   preferably H, halo, cyano and C₁₋₂-alkyl substituted with            R², or wherein R^(a) and R^(b) together form C₃-C₄            cycloalkyl, more preferably H, halo and C₁-C₂-alkyl, even            more preferably H;

-   wherein R^(z) is selected from C₁-C₄ alkylenyl, where one of the CH₂    groups may be substituted with an oxygen atom or an —NH—,    -   preferably C₁-C₂ alkylenyl, where one of the CH₂ groups may be        substituted with an oxygen atom or an —NH— more preferably C₁-C₂        alkylenyl;

-   wherein R^(d) is cycloalkyl,    -   preferably C₃-C₆ cycloalkyl;

-   wherein R is selected from    -   a) substituted or unsubstituted 5-6 membered heterocyclyl,        -   preferably substituted or unsubstituted 5-6 membered            heteroaryl comprising one or more nitrogen atoms,            -   more preferably 4-pyrazolyl, triazolyl, 4-pyridyl,                4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,                4-pyridazinyl, or 6-pyridazinyl,                -   even more preferably 4-pyridyl, 4-pyrimidinyl and                    4-pyridazinyl,                -   even more preferably 4-pyridyl, and    -   b) substituted or unsubstituted fused 9-, 10- or 11-membered        heterocyclyl,        -   preferably substituted or unsubstituted 9-10 membered fused            heteroaryl comprising one or more nitrogen atoms,            -   more preferably indazolyl, quinolinyl, isoquinolinyl, or                quinazolinyl,                -   even more preferably indazolyl, 4-quinolyl,                    5-quinolyl, 6-quinolyl, 4-isoquinolyl,                    5-isoquinolyl, and 6-isoquinolyl,        -   wherein substituted R is substituted with one or more            substituents independently selected from halo, —OR³, —SR³,            —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³,            —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted            5-6 membered heterocyclyl, optionally substituted phenyl,            lower alkyl substituted with R², cyano, nitro, lower alkenyl            and lower alkynyl;            -   preferably halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³,                —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³,                —NR³C(O)NR³R³, cycloalkyl, optionally substituted 5-6                membered heterocyclyl, optionally substituted phenyl,                C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, nitro and                C₁₋₂-haloalkyl;

-   wherein R¹ is selected from    -   a) substituted or unsubstituted 6-10 membered aryl,        -   preferably phenyl, naphthyl, indenyl, or tetrahydronaphthyl,            -   more preferably phenyl,    -   b) substituted or unsubstituted 5-6 membered heterocyclyl,        -   preferably 5-6 membered heteroaryl,            -   more preferably thienyl, pyridyl, pyrimidinyl,                pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,                thiadiazolyl, furyl, or pyrrolyl,    -   c) substituted or unsubstituted 9-10 membered fused        heterocyclyl,        -   preferably 9-10 membered fused heteroaryl,            -   more preferably indazolyl, indolyl,                2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl,                tetrahydroquinolyl, benzodioxanyl, or quinazolinyl,    -   d) cycloalkyl, and    -   e) cycloalkenyl        -   wherein substituted R¹ is substituted with one or more            substituents independently selected from halo, —OR³, —SR³,            —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄ alkylenylR¹⁴),            —SO₂R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionally            substituted cycloalkyl, optionally substituted 5-6 membered            heterocyclyl, optionally substituted phenyl, lower alkyl            substituted with R², cyano, nitro, lower alkenyl and lower            alkynyl,            -   preferably R¹ is unsubstituted or substituted with one                or more substituents independently selected from halo,                —OR³, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,                —NH(C₁-C₂ alkylenylR³), —(C₁-C₂ alkylenyl)NR³R³,                —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionally                substituted cycloalkyl, optionally substituted 5-6                membered heterocyclyl, optionally substituted phenyl,                optionally substituted phenyl-C₁₋₂-alkylenyl, optionally                substituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl,                C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, nitro and                C₁₋₂-haloalkyl,                -   more preferably R¹ is unsubstituted or substituted                    with one or more substituents selected from chloro,                    fluoro, bromo, methoxy, phenyloxy, benzyl,                    methylthio, methyl, ethyl, trifluoromethyl,                    difluoromethyl, pentafluoroethyl, hydroxymethyl,                    cyano, carboxy, aminocarbonyl, methylcarbonyl,                    amino, methylamino, cyclopropyl, cyclohexyl,                    piperidinyl, morpholinyl, N-methylpiperazinyl,                    N-ethylpiperazinyl, morpholinylmethyl,                    methylpiperidinylmethyl, methylpiperazinylmethyl,                    methylaminothiocarbonyl, N-methylamino-methylenyl,                    optionally substituted phenyl, N,N-diethylamino, or                    N,N-dimethylamino;

-   wherein R² is one or more substituents independently selected from    H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,    —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally    substituted phenylalkylenyl, optionally substituted 5-6 membered    heterocyclyl, optionally substituted heteroarylalkylenyl, optionally    substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower    carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl,    lower alkylaminoalkyl and lower haloalkyl,    -   preferably R² is one or more substituents independently selected        from H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³,        —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally        substituted 5-6 membered heterocyclyl, optionally substituted        phenyl, C₁₋₂-alkyl, cyano, C₁₋₂-hydroxyalkyl, C₁₋₃-carboxyalkyl,        nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl and C₁₋₂-haloalkyl;

-   wherein R³ is selected from H, lower alkyl, phenyl, 5-6 membered    heterocyclyl, C₃-C₆ cycloalkyl, and lower haloalkyl,    -   preferably H, C₁₋₂-alkyl, phenyl, C₃-C₆ cycloalkyl, and        C₁₋₂-haloalkyl,        -   more preferably H, methyl, phenyl, cyclopropyl, cyclohexyl,            and trifluoromethyl;

-   wherein R⁴ is independently selected from C₂₋₄-alkylenyl,    C₂₋₄-alkenylenyl and C₂₋₄-alkynylenyl, where one of the CH₂ groups    may be substituted with an oxygen atom or an —NH—,    -   preferably C₂₋₃-alkylenyl where one of the CH₂ groups may be        substituted with an oxygen atom or an —NH—, more preferably        C₂-C₃ alkylenyl;

-   wherein R⁵ is selected from H, lower alkyl, phenyl and lower    aralkyl,    -   preferably H, methyl or ethyl;

-   wherein R⁶ is selected from H or C₁₋₆-alkyl,    -   preferably H or C₁₋₂ alkyl; and

-   wherein R^(c) is selected from H, methyl and optionally substituted    phenyl;

-   wherein R¹⁴ is selected from H, phenyl, 5-6 membered heterocyclyl    and C₃-C₆ cycloalkyl;

-   wherein p is 0 to 2, preferably p is 2;

-   and pharmaceutically acceptable salts thereof;    provided A is not naphthyl when X is —C(O)NH— and when R¹ is phenyl    when Y is —NHCH₂— and when R is 4-pyridyl; further provided A is not    pyridyl when X is —C(O)NH— and when R¹ is    4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y is    —N(CH₃)— and when R is 4-methylpiperidinyl; further provided A is    not pyridyl when X is —C(O)NH— and when Y is —NHCH₂— and when R is    4-pyridylpiperidin-4-yl, 1-tertbutylpiperidin-4-yl,    1-isopropylpiperidin-4-yl or 1-cycloalkylpiperidin-4-yl; further    provided A is not pyridyl when X is —C(O)NH— and when R¹ is    4-[3-(3-pyridyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y    is —NHCH₂— and when R is 4-pyridyl; and further provided R is not    unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl.

The invention also relates to compounds of Formula II

-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, triazolyl, pyridazinyl,            indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl,            naphthyridinyl or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;-   preferably one or more substituents independently selected from H,    chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,    trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl,    unsubstituted or substituted phenyl and unsubstituted or substituted    heteroaryl selected    -   from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and-   wherein R⁶ is H or C₁₋₂-alkyl;-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula III

-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,            isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl            or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;    -   preferably one or more substituents independently selected from        H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,        trifluoromethyl, methoxy, ethoxy, trifluoromethoxy,        carboxymethyl, unsubstituted or substituted phenyl and        unsubstituted or substituted heteroaryl selected        -   from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;            and-   wherein R⁶ is H or C₁₋₂-alkyl;-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula IV

-   wherein A³ is selected from CR² and N;-   wherein A⁴ is selected from CR² and N; provided one of A³ and A⁴ is    not CR²;-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,            isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl            or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;    -   preferably one or more substituents independently selected from        H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,        trifluoromethyl, methoxy, ethoxy, trifluoromethoxy,        carboxymethyl, unsubstituted or substituted phenyl and        unsubstituted or substituted heteroaryl selected    -   from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and-   wherein R⁶ is H or C₁₋₂-alkyl;-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula V

-   wherein A⁵ is selected from S, O and NR⁶;-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,            isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl            or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;    -   preferably one or more substituents independently selected from        H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,        trifluoromethyl, methoxy, ethoxy, trifluoromethoxy,        carboxymethyl, unsubstituted or substituted phenyl and        unsubstituted or substituted heteroaryl selected        -   from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;            and-   wherein R⁶ is H or C₁₋₂-alkyl;-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula VI

-   wherein A⁵ is selected from S, O and NR⁶;-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,            isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl            or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;    -   preferably one or more substituents independently selected from        H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,        trifluoromethyl, methoxy, ethoxy, trifluoromethoxy,        carboxymethyl, unsubstituted or substituted phenyl and        unsubstituted or substituted heteroaryl selected        -   from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;            and-   wherein R⁶ is H or C₁₋₂-alkyl;-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula VII

-   wherein A⁵ is selected from S, O and NR⁶;-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,            isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl            or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;    -   preferably one or more substituents independently selected from        H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,        trifluoromethyl, methoxy, ethoxy, trifluoromethoxy,        carboxymethyl, unsubstituted or substituted phenyl and        unsubstituted or substituted heteroaryl selected        -   from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;            and-   wherein R⁶ is H or C₁₋₂-alkyl;-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula VIII

-   wherein A⁵ is selected from S, O and NR⁶;-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,            isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl            or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;    -   preferably one or more substituents independently selected from        H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl,        trifluoromethyl, methoxy, ethoxy, trifluoromethoxy,        carboxymethyl, unsubstituted or substituted phenyl and        unsubstituted or substituted heteroaryl selected        -   from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;            and-   wherein R⁶ is H or C₁₋₂-alkyl;-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula IX

-   wherein A⁵ is selected from S, O and NR⁶;-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,            isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl            or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;        -   preferably one or more substituents independently selected            from H, chloro, fluoro, bromo, amino, hydroxy, methyl,            ethyl, propyl, trifluoromethyl, methoxy, ethoxy,            trifluoromethoxy, carboxymethyl, unsubstituted or            substituted phenyl and unsubstituted or substituted            heteroaryl selected        -   from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl;            and-   wherein R⁶ is H or C₁₋₂-alkyl;-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula X

-   wherein A⁵ is selected from S, O and NR⁶;-   wherein A⁶ is selected from N and CR²;-   wherein R^(a) and R^(b) are independently selected from H, halo,    C₁₋₄-alkyl and —N(R⁶)₂,    -   preferably H;-   wherein n is 0-2;    -   preferably 1-2;-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl,            isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl            or quinozalinyl,    -   where R is substituted with one or more substituents selected        from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl and        C₁₋₆-alkoxy,        -   preferably substituted with one or more substituents            selected from chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted aryl,    5-6-membered heteroaryl and 9-10 membered fused heteroaryl,    -   preferably unsubstituted or substituted phenyl,        tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl,        pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl,        quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl,        benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,        -   wherein R¹ is substituted with one or more substituents            selected from halo, C₁₋₆-alkyl, optionally substituted            C₃₋₆-cycloalkyl, optionally substituted phenyl,            C₁₋₆-haloalkoxy, optionally substituted phenyloxy, benzyl,            optionally substituted 5-6 membered            heterocyclyl-C₁-C₂-alkylenyl, optionally substituted            heteroaryl, optionally substituted heteroaryloxy,            C₁₋₆-haloalkyl, and C₁₋₆-alkoxy,            -   preferably chloro, fluoro, amino, hydroxy, cyclohexyl,                phenylmethyl, morpholinylmethyl,                methylpiperidinylmethyl, methylpiperazinylmethyl, ethyl,                propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   unsubstituted or substituted aryl and        -   unsubstituted or substituted 5-6 membered heteroaryl;        -   preferably one or more substituents independently selected            from H, chloro, fluoro, bromo, amino, hydroxy, methyl,            ethyl, propyl, trifluoromethyl, methoxy, ethoxy,            trifluoromethoxy, carboxymethyl, unsubstituted or            substituted phenyl and unsubstituted or substituted            heteroaryl selected            -   from thienyl, furanyl, pyridyl, imidazolyl, and                pyrazolyl;-   wherein    -   a) R¹⁰ is

-   -    R¹¹ is

-   -    R¹² is H, and R¹³ is H; or    -   b) R¹⁰ is

-   -    R¹¹ is

-   -    R¹² is H, and R¹³ is H; or    -   c) R¹⁰ is H, R¹¹ is

-   -    R¹² is

-   -    and R¹³ is H; or    -   d) R¹⁰ is H, R¹¹ is

-   -    R¹² is

-   -    and R¹³ is H; or    -   e) R¹⁰ is H, R¹¹ is H, R¹² is

-   -    and R¹³ is

-   -    or    -   f) R¹⁰ is H, R¹¹ is H, R¹² is

-   -    and R¹³ is

-   -    and

-   wherein R⁶ is H or C₁₋₂-alkyl;

-   and pharmaceutically acceptable isomers and salts thereof.

The invention also relates to compounds of Formula II′

-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl,    -   preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl,        triazolyl, and pyridazinyl,        -   more preferably 4-pyridyl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        heterocyclyl    -   preferably indolyl, isoindolyl, indazolyl, quinolyl,        isoquinolyl, benzotriazolyl, 2,3-dihydrobenzofuryl,        2-oxo-1,2-dihydroquinol-7-yl, naphthyridinyl and quinozalinyl,    -   where substituted R is substituted with one or more substituents        selected from halo, amino, hydroxy, oxo, C₁₋₆-alkyl,        C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally substituted        heterocyclyl-C₁₋₆-alkoxy, optionally substituted        heterocyclyl-C₁₋₆-alkylamino, optionally substituted        heterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,        C₁₋₆-alkylamino-C₁₋₆-alkoxy,        C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy, and optionally        substituted heterocyclyl-C₂₋₄-alkynyl,        -   preferably chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, dimethylaminopropynyl,            1-methylpiperidinylmethoxy, dimethylaminoethoxyethoxy,            methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted    -   aryl, preferably phenyl, tetrahydronaphthyl, indanyl, indenyl,        and naphthyl,    -   cycloalkyl, preferably cyclohexyl,    -   5-6 membered heteroaryl, preferably isoxazolyl, pyrazolyl,        thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and        pyridazinyl, and    -   9-10 membered bicyclic and 13-14 membered tricyclic        heterocyclyl, preferably 1,2-dihydroquinolyl,        1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl,        isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl,        quinozalinyl, benzo[d]isothiazolyl,        2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,        5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,        tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl,        benzodioxanyl, benzothienyl, benzofuryl, dihydro-benzimidazolyl,        benzimidazolyl, benzoxazolyl and benzthiazolyl;-   wherein substituted R¹ is substituted with one or more substituents    selected from halo, C₁₋₆-alkyl, optionally substituted    C₃₋₆-cycloalkyl, optionally substituted phenyl, optionally    substituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally    substituted 4-6 membered heterocyclyl-C₁-C₄-alkylenyl, optionally    substituted 4-6 membered heterocyclyl-C₂-C₄-alkenylenyl, optionally    substituted 4-6 membered heterocyclyl, optionally substituted    phenyloxy, optionally substituted 4-6 membered heterocyclyloxy,    optionally substituted 4-6 membered heterocyclyl-C₁₋₄-alkyloxy,    optionally substituted 4-6 membered heterocyclylsulfonyl, optionally    substituted 4-6 membered heterocyclylamino, optionally substituted    4-6 membered heterocyclylcarbonyl, optionally substituted 4-6    membered heterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl,    C₁₋₄-aminoalkyl, nitro, amino, —NHC(O)NH₂, alkylcarbonylamino,    hydroxy, oxo, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl,    halosulfonyl, C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,    C₁₋₃-alkylamino-C₁₋₃-alkoxy,    C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy, C₁₋₄-alkoxycarbonyl,    C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl, C₁₋₄-hydroxyalkyl,

-    and C₁₋₄-alkoxy,    -   preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano,        aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,        4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,        morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,        1-methylpiperazin-4-ylpropyl, morpholinylpropyl,        piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl,        2-methyl-2-(1-methylpiperidin-4-yl)ethyl, morpholinylethyl,        1-(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl,        1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,        1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,        1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,        1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl,        pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl,        1-Boc-pyrrolidin-2-ylpropyl, pyrrolidin-1-ylmethyl,        pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl,        pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl,        methylsulfonyl, methylcarbonyl, Boc,        piperidin-1-ylmethylcarbonyl,        4-methylpiperazin-1-ylcarbonylethyl, methoxycarbonyl,        aminomethylcarbonyl, dimethylaminomethylcarbonyl,        3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,        4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,        1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),        imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl,        hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl,        tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl,        nonafluorobutyl, dimethylaminopropyl,        1,1-di(trifluoromethyl)-1-hydroxymethyl,        1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,        1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl,        1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl,        2-aminoethyl, 1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)        ethyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy,        azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy,        pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy,        pyrrol-1-ylmethoxy, 1-methyl-pyrrol-2-ylmethoxy,        1-isopropyl-pyrrol-2-ylmethoxy, 1-Boc-piperidin-4-ylmethoxy,        piperidin-4-ylmethoxy, 1-methylpiperidin-4-yloxy, isopropoxy,        methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   hydroxy,        -   amino,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₂-alkylamino,        -   aminosulfonyl,        -   C₃₋₆-cycloalkyl,        -   cyano,        -   C₁₋₂-hydroxyalkyl,        -   nitro,        -   C₂₋₃-alkenyl,        -   C₂₋₃-alkynyl,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   5-6-membered heterocyclyl-C₁₋₆-alkylamino,        -   unsubstituted or substituted phenyl and        -   unsubstituted or substituted 5-6 membered heterocyclyl;    -   preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl,        ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl,        cyano, hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy,        ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino,        propynyl, unsubstituted or substituted phenyl and unsubstituted        or substituted heteroaryl selected from thienyl,        -   furanyl, pyridyl, imidazolyl, and pyrazolyl;-   wherein R⁴ is selected from a direct bond, C₁₋₄-alkyl, and

-   -   preferably a direct bond, ethyl, butyl, and

-   wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,    C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl and    C₁₋₂-alkylamino-C₁₋₂-alkyl,    -   preferably methylenyl, ethylenyl,

-   -    and aminoethylenyl;

-   wherein R^(e) and R^(f) are independently selected from H and    C₁₋₂-haloalkyl,    -   preferably trifluoromethyl; and

-   wherein R⁷ is selected from H, C₁₋₃-alkyl, optionally substituted    phenyl, optionally substituted phenyl-C₁₋₃-alkyl, optionally    substituted 4-6 membered heterocyclyl, optionally substituted 4-6    membered heterocyclyl-C₁-C₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,    C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl;

-   provided R² is not H, or provided R¹ is not heteroaryl or aryl or    provided R is substituted with optionally substituted    heterocyclyl-C₁₋₆-alkoxy, optionally substituted    heterocyclyl-C₁₋₆-alkylamino, optionally substituted    heterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,    C₁₋₆-alkylamino-C₁₋₆-alkoxy,    C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy, or optionally substituted    heterocyclyl-C₂₋₄-alkynyl, or R¹ is substituted with optionally    substituted phenyloxy, optionally substituted 5-6 membered    heterocyclyloxy, optionally substituted 5-6 membered    heterocyclylsulfonyl, optionally substituted 5-6 membered    heterocyclylamino, optionally substituted 5-6 membered    heterocyclylcarbonyl, optionally substituted 5-6 membered    heterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy, or    C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy; further provided R is not    3-pyridyl when R^(z) is CH₂;

-   and pharmaceutically acceptable isomers and derivatives thereof.

The invention also relates to compounds of Formula XI

-   wherein R is selected from    -   a) unsubstituted or substituted 5- or 6-membered        nitrogen-containing heteroaryl,        -   preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl,            triazolyl, and pyridazinyl,            -   more preferably 4-pyridyl, and    -   b) unsubstituted or substituted 9- or 10-membered fused        heteroaryl        -   preferably indolyl, isoindolyl, indazolyl, quinolyl,            isoquinolyl, benzotriazolyl, naphthyridinyl and            quinozalinyl,    -   where substituted R is substituted with one or more substituents        selected from halo, amino, hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl,        C₁₋₆-alkoxy, optionally substituted heterocyclyl-C₁₋₆-alkoxy,        optionally substituted heterocyclyl-C₁₋₆-alkylamino, optionally        substituted heterocyclyl-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₂₋₄-alkynyl, C₁₋₆-alkylamino-C₁₋₆-alkoxy,        C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy, and optionally        substituted heterocyclyl-C₂₋₄-alkynyl,        -   preferably chloro, fluoro, amino, hydroxy, methyl, ethyl,            propyl, trifluoromethyl, dimethylaminopropynyl,            1-methylpiperidinylmethoxy, dimethylaminoethoxyethoxy,            methoxy and ethoxy;-   wherein R¹ is selected from unsubstituted or substituted    -   aryl,    -   cycloalkyl,    -   5-6 membered heteroaryl and    -   9-10 membered bicyclic and 13-14 membered tricyclic        heterocyclyl,    -   preferably phenyl, tetrahydronaphthyl, indanyl, indenyl,        naphthyl, cyclohexyl, isoxazolyl, pyrazolyl, thiazolyl,        thiadiazolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl,        1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,        isoquinolyl, quinolyl, indolyl, isoindolyl,        2,3-dihydro-1H-indolyl, naphthyridinyl, quinozalinyl,        benzo[d]isothiazolyl,        2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,        5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,        tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl,        benzodioxanyl, benzothienyl, benzofuryl, dihydro-benzimidazolyl,        benzimidazolyl, benzoxazolyl and benzthiazolyl,        -   specifically 4-6 membered saturated or partially            un-saturated monocyclic heterocyclyl,            -   9-10 membered saturated or partially un-saturated                bicyclic heterocyclyl, and            -   13-14 membered saturated or partially un-saturated                tricyclic heterocyclyl,            -   more specifically 1,2-dihydroquinolyl,                1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-1H-indolyl,                benzo[d]isothiazolyl, dihydro-benzimidazolyl,                2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,                5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, and                tetrahydroquinolinyl,-   wherein substituted R¹ is substituted with one or more substituents    selected from halo, C₁₋₆-alkyl, optionally substituted    C₃₋₆-cycloalkyl, optionally substituted phenyl, optionally    substituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally    substituted 4-6 membered heterocyclyl-C₁-C₄-alkyl, optionally    substituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionally    substituted 4-6 membered heterocyclyl, optionally substituted    phenyloxy, optionally substituted 4-6 membered heterocyclyloxy,    optionally substituted 4-6 membered heterocyclyl-C₁-C₄-alkoxy,    optionally substituted 4-6 membered heterocyclylsulfonyl, optionally    substituted 4-6 membered heterocyclylamino, optionally substituted    4-6 membered heterocyclylcarbonyl, optionally substituted 5-6    membered heterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl,    C₁₋₄-aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl,    C₁₋₂-alkylsulfonyl, halosulfonyl, C₁₋₄-alkylcarbonyl,    C₁₋₃-alkylamino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy,    C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy, C₁₋₄-alkoxycarbonyl,    C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl, C₁₋₄-hydroxyalkyl,

-    and C₁₋₄-alkoxy,    -   preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano,        aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,        4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,        morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,        1-methylpiperazin-4-ylpropyl, morpholinylpropyl,        piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl,        2-methyl-2-(1-methylpiperidin-4-yl)ethyl, morpholinylethyl,        1-(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl,        1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,        1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,        1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,        1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl,        pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl,        1-Boc-pyrrolidin-2-ylpropyl, pyrrolidin-1-ylmethyl,        pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl,        pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl,        methylsulfonyl, methylcarbonyl, Boc,        piperidin-1-ylmethylcarbonyl,        4-methylpiperazin-1-ylcarbonylethyl, methoxycarbonyl,        aminomethylcarbonyl, dimethylaminomethylcarbonyl,        3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,        4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,        1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),        imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl,        hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl,        tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl,        nonafluorobutyl, dimethylaminopropyl,        1,1-di(trifluoromethyl)-1-hydroxymethyl,        1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,        1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl,        1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl,        2-aminoethyl, 1-(N-isopropylamino)ethyl,        2-(N-isopropylamino)ethyl, dimethylaminoethoxy, 4-chlorophenoxy,        phenyloxy, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy,        pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy,        pyrrol-1-ylmethoxy, 1-methyl-pyrrol-2-ylmethoxy,        1-isopropyl-pyrrol-2-ylmethoxy, 1-Boc-piperidin-4-ylmethoxy,        piperidin-4-ylmethoxy, 1-methylpiperidin-4-yloxy, isopropoxy,        methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   hydroxy,        -   amino,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₂-alkylamino,        -   aminosulfonyl,        -   C₃₋₆-cycloalkyl,        -   cyano,        -   C₁₋₂-hydroxyalkyl,        -   nitro,        -   C₂₋₃-alkenyl,        -   C₂₋₃-alkynyl,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   5-6-membered heterocyclyl-C₁₋₆-alkylamino,        -   unsubstituted or substituted phenyl and        -   unsubstituted or substituted 5-6 membered heterocyclyl,-   preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl,    propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano,    hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy,    trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl,    unsubstituted or substituted phenyl and unsubstituted or substituted    heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and    pyrazolyl,    -   specifically chloro, fluoro, bromo, amino, hydroxy, methyl,        ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl,        cyano, hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy,        ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino,        propynyl, unsubstituted or substituted phenyl and unsubstituted        or substituted heteroaryl selected from thienyl, furanyl,        pyridyl, imidazolyl, and pyrazolyl;-   wherein R⁴ is selected from a direct bond, C₁₋₄-alkyl, and

-   preferably a direct bond, ethyl, butyl, and

-   wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,    C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl and    C₁₋₂-alkylamino-C₁₋₂-alkyl,    -   preferably methylenyl, ethylenyl,

-   -    and aminoethylenyl;

-   wherein R^(e) and R^(f) are independently selected from H and    C₁₋₂-haloalkyl,    -   preferably trifluoromethyl; and

-   wherein R⁷ is selected from H, C₁₋₃-alkyl, optionally substituted    phenyl, optionally substituted phenyl-C₁₋₃-alkyl, optionally    substituted 4-6 membered heterocyclyl, optionally substituted 4-6    membered heterocyclyl-C₁-C₃-alkyl, C₁₋₃-alkoxy-C₁₋₂-alkyl and    C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl;

-   provided R¹ is substituted with optionally substituted phenyloxy,    optionally substituted 4-6 membered heterocyclyloxy, optionally    substituted 4-6 membered heterocyclyl-C₁₋₄-alkoxy, optionally    substituted 4-6 membered heterocyclylsulfonyl, optionally    substituted 4-6 membered heterocyclylamino, optionally substituted    4-6 membered heterocyclylcarbonyl, optionally substituted 4-6    membered heterocyclyl-C₁₋₄-alkylcarbonyl,    C₁₋₃-alkylamino-C₁₋₃-alkoxy, or    C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy; further provided R is not    3-pyridyl when R⁵ is CH₂;

-   and pharmaceutically acceptable isomers and derivatives thereof.

The invention also relates to compounds of Formula XII

-   wherein R¹ is selected from unsubstituted or substituted    -   aryl, preferably phenyl, tetrahydronaphthyl, indanyl, indenyl,        and naphthyl,    -   cycloalkyl, preferably cyclohexyl,    -   5-6 membered heteroaryl, preferably isoxazolyl, pyrazolyl,        thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and        pyridazinyl, and    -   9-10 membered bicyclic and 13-14 membered tricyclic        heterocyclyl, preferably 1,2-dihydroquinolyl,        1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl,        isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl,        quinozalinyl, benzo[d]isothiazolyl,        2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,        5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,        tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl,        benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl,        benzoxazolyl and benzthiazolyl;-   wherein substituted R¹ is substituted with one or more substituents    selected from halo, C₁₋₆-alkyl, optionally substituted    C₃₋₆-cycloalkyl, optionally substituted phenyl, optionally    substituted phenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally    substituted 4-6 membered heterocyclyl-C₁-C₄-alkyl, optionally    substituted 4-6 membered heterocyclyl-C₂-C₄-alkenyl, optionally    substituted 4-6 membered heterocyclyl, optionally substituted    phenyloxy, optionally substituted 4-6 membered heterocyclyloxy,    optionally substituted 4-6 membered heterocyclyl-C₁-C₄-alkoxy,    optionally substituted 4-6 membered heterocyclylsulfonyl, optionally    substituted 4-6 membered heterocyclylamino, optionally substituted    4-6 membered heterocyclylcarbonyl, optionally substituted 5-6    membered heterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl,    C₁₋₄-aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl,    C₁₋₂-alkylsulfonyl, halosulfonyl, C₁₋₄-alkylcarbonyl,    C₁₋₃-alkylamino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkoxy,    C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy, C₁₋₄-alkoxycarbonyl,    C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl, C₁₋₄-hydroxyalkyl,

-    and C₁₋₄-alkoxy,    -   preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano,        aminoethyl, Boc-aminoethyl, hydroxy, oxo, aminosulfonyl,        4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl,        morpholinylmethyl, 1-methylpiperazin-4-ylmethyl,        1-methylpiperazin-4-ylpropyl, morpholinylpropyl,        piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl,        2-methyl-2-(1-methylpiperidin-4-yl)ethyl, morpholinylethyl,        1-(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl,        1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl,        1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl,        1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl,        1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl,        pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl,        1-Boc-pyrrolidin-2-ylpropyl, pyrrolidin-1-ylmethyl,        pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl,        pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl,        methylsulfonyl, methylcarbonyl, Boc,        piperidin-1-ylmethylcarbonyl,        4-methylpiperazin-1-ylcarbonylethyl, methoxycarbonyl,        aminomethylcarbonyl, dimethylaminomethylcarbonyl,        3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl,        4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl,        1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl),        imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl,        hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl,        tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl,        nonafluorobutyl, dimethylaminopropyl,        1,1-di(trifluoromethyl)-1-hydroxymethyl,        1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl,        1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl,        1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl,        2-aminoethyl, 1-(N-isopropylamino)ethyl,        2-(N-isopropylamino)ethyl, dimethylaminoethoxy, 4-chlorophenoxy,        phenyloxy, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy,        pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy,        pyrrol-1-ylmethoxy, 1-methyl-pyrrol-2-ylmethoxy,        1-isopropyl-pyrrol-2-ylmethoxy, 1-Boc-piperidin-4-ylmethoxy,        piperidin-4-ylmethoxy, 1-methylpiperidin-4-yloxy, isopropoxy,        methoxy and ethoxy;-   wherein R² is one or more substituents independently    -   selected from        -   H,        -   halo,        -   hydroxy,        -   amino,        -   C₁₋₆-alkyl,        -   C₁₋₆-haloalkyl,        -   C₁₋₆-alkoxy,        -   C₁₋₂-alkylamino,        -   aminosulfonyl,        -   C₃₋₆-cycloalkyl,        -   cyano,        -   C₁₋₂-hydroxyalkyl,        -   nitro,        -   C₂₋₃-alkenyl,        -   C₂₋₃-alkynyl,        -   C₁₋₆-haloalkoxy,        -   C₁₋₆-carboxyalkyl,        -   5-6-membered heterocyclyl-C₁₋₆-alkylamino,        -   unsubstituted or substituted phenyl and        -   unsubstituted or substituted 5-6 membered heterocyclyl,    -   preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl,        ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl,        cyano, hydroxymethyl, nitro, propenyl, trifluoromethyl, methoxy,        ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino,        propynyl, unsubstituted or substituted phenyl and unsubstituted        or substituted heteroaryl selected from thienyl, fury, pyridyl,        imidazolyl, and pyrazolyl;-   wherein R^(e) and R^(f) are independently selected from H and    C₁₋₂-haloalkyl,    -   preferably trifluoromethyl;-   wherein R⁷ is selected from H, C₁₋₃-alkyl, optionally substituted    phenyl, optionally substituted phenyl-C₁₋₃-alkyl, optionally    substituted 4-6 membered heterocyclyl, optionally substituted 4-6    membered heterocyclyl-C₁-C₃-alkyl, C₁₋₃-alkoxy-C₁₋₂-alkyl and    C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; and-   wherein R²⁰ is one or more substituents selected from halo, amino,    hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally    substituted heterocyclyl-C₁₋₆-alkoxy, optionally substituted    heterocyclyl-C₁₋₆-alkylamino, optionally substituted    heterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,    C₁₋₆-alkylamino-C₁₋₆-alkoxy,    C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy, and optionally substituted    heterocyclyl-C₂₋₄-alkynyl,    -   preferably chloro, fluoro, amino, hydroxy, methyl, ethyl,        propyl, trifluoromethyl, dimethylaminopropynyl,        1-methylpiperidinylmethoxy, dimethylaminoethoxyethoxy, methoxy        and ethoxy;-   and pharmaceutically acceptable isomers and derivatives thereof.

A family of specific compounds of particular interest within Formula Iconsists of compounds and pharmaceutically-acceptable derivativesthereof as follows:

-   N-(4-Isopropylphenyl)    {2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3-(Isopropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3-Isoquinolyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-Isopropylphenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)phenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(Methylpropyl)phenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;-   {2-[(2-(3-Pyridyl)ethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;-   {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}carboxamide;-   N-[5-(tert-Butyl)isoxazol-3-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[5-(tert-Butyl)-1-methylpyrazol-3-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)(1,3-thiazol-2-yl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[5-(tert-Butyl)(1,3,4-thiadiazol-2-yl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(4-Hydroxybutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[2-(4-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   5-Bromo-N-[2-(4-chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-Phenoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-Methoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-Hydroxy-3-ethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-(tert-Butyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3-(Trifluoromethyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3-Ethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3,4-Dimethylphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(1,3-Benzodioxol-5-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-Methylphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-Hydroxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-Bromophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3,4-Dichlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-(Fluorosulfonyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(3,5-(Dimethoxy)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(2,4-Dichlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(2-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(2-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(4-(Aminosulphonyl)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(2-Thienyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(Pyridin-2-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)}carboxamide;-   N-[2-(Pyridin-3-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-[2-(Pyridin-4-yl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-(4-Phenylbutyl)-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   N-(2-Hydroxy-3-phenoxypropyl)-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide;-   {6-Chloro-5-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;-   {5-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;-   2-[(Pyridin-4-ylmethyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl](3-pyridyl)carboxamide;-   N-(3,4-Dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(Morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-{2-[(tert-Butoxy)carbonylamino]ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(2-Aminoethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3-Amino-4-(tert-butyl)phenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(Isopropyl)phenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3-Aminosulfonyl-4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3-[(4-Methylpiperazinyl)sulfonyl]phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(1,1,2,2,2-Pentafluoroethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(1,1,2,2,3,3,4,4,4-Nonafluorobutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(Isopropyl)phenyl]{2-[(2-(1,2,4-triazolyl)ethyl)amino](3-pyridyl)}carboxamide;-   (2-{[2-(2-Pyridylamino)ethyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;-   {2-[(1-(2-Pyridyl)pyrrolidin-3-yl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;-   2-[(Pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-nicotinamide-   {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(8-quinolyl)carboxamide    hydrochloride;-   N-[4-(4-Chlorophenoxy)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(2,3,4-trifluorophenyl)carboxamide    hydrochloride;-   N-(2-Naphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(2-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(5,6,7,8-tetrahydronaphthyl)    carboxamide hydrochloride;-   N-(2H-Benzo[3,4-d]1,3-dioxolen-5-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-Naphthyl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-[3-Benzylphenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(Cyclohexylethyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(Cyclohexylethyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-Indan-2-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-[4-(tert-Butyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-sec-Butyl-phenyl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(4-Methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-trifluoromethoxy)phenyl]carboxamide;-   N-(4-Ethylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-Butylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-Iodophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3-(Hydroxyethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3-Ethylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   Ethyl    2-methyl-5-[3-({2-[(4-pyridylmethyl)amino](3-pyridyl)}carbonylamino)phenyl]furan-3-carboxylate;-   N-(3-Phenylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-Benzylphenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(6-Ethyl(2-pyridyl)){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(6-Propyl(2-pyridyl)){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)(2-pyridyl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3-Hydroxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(Methylethyl)(2-pyridyl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3,5-bis(Trifluoromethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-[4-Chloro-3-(trifluoromethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(3-Chlorophenyl){2-[(2-(4-pyridyl)ethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(4-Phenoxyphenyl){2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;-   2-[(Benzo[b]thiophen-3-ylmethyl)amino](3-pyridyl)}-N-(4-phenoxyphenyl)carboxamide;-   N-(4-Phenoxyphenyl){2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(Methylsulfonyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(1-Acetylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-Indolin-6-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-Indol-6-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-Indol-5-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-Indol-7-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3-(tert-Butyl)pyrazol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3-Phenylpyrazol-5-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-{2-[2-(dimethylamino)ethoxy]-5-(tert-butyl)phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}formamide;-   N-[1-(1-Methyl-(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[1-(1-Methyl-(4-piperidyl))indolin-6-yl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide;-   N-[1-(2-Piperidylethyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[1-(2-Piperidylacetyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3,3-Dimethyl-1-(1-methyl(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3-(1-Methyl-(4-piperidyl))indol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(1,1-Dimethyl-3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)phenyl]{2-[({2-[(1-methyl(4-piperidyl))-methoxy](4-pyridyl)}methyl)amino](3-pyridyl)}carboxamide;-   N-(4-Bromo-2-fluorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide;-   {2-[({2-[3-(Dimethylamino)prop-1-ynyl](4-pyridyl)}methyl)amino](3-pyridyl)}-N-[4-(tert-butyl)phenyl]carboxamide;-   (2-{[(2-Methoxy(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide;-   N-{3-[3-(Dimethylamino)propyl]-5-(trifluoromethyl)phenyl}-{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)-3-(3-piperid-1-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)-3-(3-pyrrolidin-1-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[3-((1E)-4-Pyrrolidin-1-ylbut-1-enyl)-4-(tert-butyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)-3-(3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[1-(2-Morpholin-4-ylethyl)indol-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)phenyl]{2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-Chlorophenyl){2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide;-   {2-[(Pyrimidin-4-ylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;-   N-[4-(Isopropyl)phenyl]{4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide;-   (2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4-(tert-butyl)phenyl]carboxamide;-   {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-(2-piperidylethoxy)-1-(trifluoromethyl)ethyl]phenyl}carboxamide;-   (2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}(4-pyridyl))methyl]amino}-6-fluoro(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide;-   N-[4-(tert-Butyl)phenyl]{6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   {6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide;-   {6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;-   N-(1-Bromo(3-isoquinolyl)){6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide;-   N-(4-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(4-Phenylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(3-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(4-Cyclohexylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(4-Imidazol-1-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-Morpholin-4-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(4-Cyanonaphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyl]carboxamide    hydrochloride;-   Methyl-4-({2-[(4-pyridylmethyl)amino]-3-pyridyl}carbonylamino)benzoate    hydrochloride;-   N-[4-(Isopropyl)phenyl]{2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide;-   N-[4-(tert-Butyl)phenyl]{2-[(6-quinolylmethyl)amino](3-pyridyl)}carboxamide;-   {2-[(6-Quinolylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide;-   N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide;-   N-phenyl{3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide;-   N-(4-chlorophenyl)-3-[(4-pyridinylmethylene)amino]-4-pyridinecarboxamide;-   N-(4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3,4-dichlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide;-   N-(3-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-pyridyl)}carboxamide;-   N-(4-chlorophenyl){3-[(6-quinolylmethyl)amino](2-pyridyl)}carboxamide;-   N-(3,4-dichlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}-carboxamide;-   N-(4-chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3,4-dichlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3-fluoro-4-methylphenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   {6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(3-fluorophenyl)carboxamide;-   N-(3-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](4-pyridyl)}carboxamide;-   N-(3-fluoro-4-methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-chlorophenyl){2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-chlorophenyl){2-[(5-quinolylmethyl)amino](3-pyridyl)}carboxamide;-   N-(4-chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamide;-   N-(4-chlorophenyl){5-(4-methoxyphenyl)-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide;    and-   N-(4-chlorophenyl){5-bromo-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide.

A family of specific compounds of particular interest within Formula II′consists of compounds and pharmaceutically-acceptable derivativesthereof as follows:

-   2-{[2-(1-Isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-{[2-(1-isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide;-   N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-nicotinamide;-   2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide;-   2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-methylpiperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide;-   N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;-   2-({2-[2-(1-Methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-{[2-ethylpyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;-   2-({2-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide;-   N-(4-Pentafluoroethyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-(2-pyridin-4-yl-ethylamino)-nicotinamide;-   N-[3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3-(4-Boc-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide;-   N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(1-Boc-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-[3,3-Dimethyl-1-(1-Boc-pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;-   2-{[2-(3-Morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;-   (S)2-{[2-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;-   N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;-   2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide;-   2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;-   N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide;-   2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;-   2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide;-   (R)N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   (R)N-[3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3-(1-Methyl-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3-tert-Butyl-4-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-trifluoromethyl-phenyl)-nicotinamide;-   2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide;-   2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-tert-butyl-phenyl)-nicotinamide;-   2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-tert-butyl-isoxazol-5-yl)-nicotinamide;-   N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;-   2-[(Pyridin-4-ylmethyl)-amino]-N-(3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-nicotinamide;-   N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(4-Imidazol-1-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;-   N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide;-   2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide;-   2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;-   N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;-   N-(4-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-[3-(1-methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    phosphate salt;-   N-(4-Morpholin-4-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(4-Cyanonaphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide,    hydrochloride;-   {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyl]carboxamide    hydrochloride;-   Methyl-({2-[(4-pyridylmethyl)amino]-3-pyridyl}carbonylamino)benzoate,    hydrochloride;-   2-[(Pyridin-4-ylmethyl)-amino]-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide;-   N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-{[2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide;-   N-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;-   N-(3-tert-Butyl-isoxazol-5-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;-   N-(3-trifluoromethylphenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;-   2-[(2,3-Dihydro-benzofuran-6-ylmethyl)-amino]-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide;-   N-[3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    hydrochloride;-   (R)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

(S)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;

-   N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[4-Pentafluoroethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-[(Pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-nicotinamide    hydrochloride;-   N-(4-Imidazol-1-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    hydrochloride;-   2-[(Pyridin-4-ylmethyl)-amino]-N-(4-tert-butyl-phenyl)-nicotinamide    hydrochloride;-   N-[4-Trifluoromethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   (S)    N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(3-Trifluoromethyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    edisylate;-   N-{4-tert-Butyl-3-[2-(1-Boc-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[4-tert-Butyl-3-(1-methyl-azetidin-3-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-{4-[1-Methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide;-   N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide;-   2-[(Pyridin-4-ylmethyl)-amino]-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide    hydrochloride;-   N-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide    hydrochloride;-   N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide;-   N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-[3,3-Dimethyl-1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-[3,3-Dimethyl-1-(pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide;-   2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamide    hydrochloride;-   N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide;-   N-(4-Pentafluoroethyl-phenyl)-2-[(pyrimidin-4-ylmethyl)-amino]-nicotinamide;-   2-{[2-(Azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)nicotinamide;-   N-(2,3,3-Trimethyl-1,1-dioxo-2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-benzamide;-   N-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    hydrochloride;-   N-[3,3-Dimethyl-1,1-dioxo-2-(2-piperidin-1-yl-ethyl)-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;    and-   N-[2-(2-Dimethylamino-ethyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

Indications

Compounds of the present invention would be useful for, but not limitedto, the prevention or treatment of angiogenesis related diseases. Thecompounds of the invention have kinase inhibitory activity, such asVEGFR/KDR inhibitory activity. The compounds of the invention are usefulin therapy as antineoplasia agents or to minimize deleterious effects ofVEGF.

Compounds of the invention would be useful for the treatment ofneoplasia including cancer and metastasis, including, but not limitedto: carcinoma such as cancer of the bladder, breast, colon, kidney,liver, lung (including small cell lung cancer), esophagus, gall-bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

Preferably, the compounds are useful for the treatment of neoplasiaselected from lung cancer, colon cancer and breast cancer.

The compounds also would be useful for treatment of ophthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerativediseases such as gastric ulcer; pathological, but non-malignant,conditions such as hemangiomas, including infantile hemaginomas,angiofibroma of the nasopharynx and avascular necrosis of bone; anddisorders of the female reproductive system such as endometriosis. Thecompounds are also useful for the treatment of edema, and conditions ofvascular hyperpermeability.

The compounds of the invention are useful in therapy of proliferativediseases. These compounds can be used for the treatment of aninflammatory rheumatoid or rheumatic disease, especially ofmanifestations at the locomotor apparatus, such as various inflammatoryrheumatoid diseases, especially chronic polyarthritis includingrheumatoid arthritis, juvenile arthritis or psoriasis arthropathy;paraneoplastic syndrome or tumor-induced inflammatory diseases, turbideffusions, collagenosis, such as systemic Lupus erythematosus,poly-myositis, dermato-myositis, systemic sclerodermia or mixedcollagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof. An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further especiallyapplicable to the treatment of inflammation, e.g. inflammatory diseaseor condition, of connective tissues including dermatomyositis andmyositis.

These compounds can be used as active agents against such disease statesas arthritis, atherosclerosis, psoriasis, hemangiomas, myocardialangiogenesis, coronary and cerebral collaterals, ischemic limbangiogenesis, wound healing, peptic ulcer Helicobacter related diseases,fractures, cat scratch fever, rubeosis, neovascular glaucoma andretinopathies such as those associated with diabetic retinopathy ormacular degeneration. In addition, some of these compounds can be usedas active agents against solid tumors, malignant ascites, hematopoieticcancers and hyperproliferative disorders such as thyroid hyperplasia(especially Grave's disease), and cysts (such as hypervascularity ofovarian stroma, characteristic of polycystic ovarian syndrome(Stein-Leventhal syndrome)) since such diseases require a proliferationof blood vessel cells for growth and/or metastasis.

Further, some of these compounds can be used as active agents againstburns, chronic lung disease, stroke, polyps, anaphylaxis, chronic andallergic inflammation, ovarian hyperstimulation syndrome, braintumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema, ascites,and other diseases where vascular hyperpermeability, effusions,exudates, protein extravasation, or edema is a manifestation of thedisease. The compounds will also be useful in treating disorders inwhich protein extravasation leads to the deposition of fibrin andextracellular matrix, promoting stromal proliferation (e.g. fibrosis,cirrhosis and carpal tunnel syndrome).

The compounds of the present invention are also useful in the treatmentof ulcers including bacterial, fungal, Mooren ulcers and ulcerativecolitis.

The compounds of the present invention are also useful in the treatmentof conditions wherein undesired angiogenesis, edema, or stromaldeposition occurs in viral infections such as Herpes simplex, HerpesZoster, AIDS, Kaposi's sarcoma, protozoan infections and toxoplasmosis,following trauma, radiation, stroke, endometriosis, ovarianhyperstimulation syndrome, systemic lupus, sarcoidosis, synovitis,Crohn's disease, sickle cell anaemia, Lyme disease, pemphigoid, Paget'sdisease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronicinflammation, chronic occlusive pulmonary disease, asthma, andinflammatory rheumatoid or rheumatic disease. The compounds are alsouseful in the reduction of sub-cutaneous fat and for the treatment ofobesity.

The compounds of the present invention are also useful in the treatmentof ocular conditions such as ocular and macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-lasercomplications, glaucoma, conjunctivitis, Stargardt's disease and Ealesdisease in addition to retinopathy and macular degeneration.

The compounds of the present invention are also useful in the treatmentof cardiovascular conditions such as atherosclerosis, restenosis,arteriosclerosis, vascular occlusion and carotid obstructive disease.

The compounds of the present invention are also useful in the treatmentof cancer related indications such as solid tumors, sarcomas (especiallyEwing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas,neuroblastoma, hematopoietic malignancies, including leukemia andlymphoma, tumor-induced pleural or pericardial effusions, and malignantascites.

The compounds of the present invention are also useful in the treatmentof diabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of this invention may also act as inhibitors of otherprotein kinases, e.g. p38, EGFR, CDK-2, CDK-5, IKK, JNK3, and thus beeffective in the treatment of diseases associated with other proteinkinases.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

As used herein, the compounds of the present invention include thepharmaceutically acceptable derivatives thereof.

DEFINITIONS

The term “treatment” includes therapeutic treatment as well asprophylactic treatment (either preventing the onset of disordersaltogether or delaying the onset of a preclinically evident stage ofdisorders in individuals).

The term “prevention” includes either preventing the onset of disordersaltogether or delaying the onset of a preclinically evident stage ofdisorders in individuals. This includes prophylactic treatment of thoseat risk of developing a disease, such as a cancer, for example.“Prophylaxis” is another term for prevention.

A “pharmaceutically-acceptable derivative” denotes any salt, ester of acompound of this invention, or any other compound which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to inhibit angiogenesis.

The phrase “therapeutically-effective” is intended to qualify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies. For example, effective neoplastic therapeuticagents prolong the survivability of the patient, inhibit therapidly-proliferating cell growth associated with the neoplasm, oreffect a regression of the neoplasm.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” and “alkylamino”, it embraces linear or branched radicalshaving one to about twelve carbon atoms. More preferred alkyl radicalsare “lower alkyl” radicals having one to about six carbon atoms.Examples of such radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and thelike. Even more preferred are lower alkyl radicals having one or twocarbon atoms. The term “alkylenyl” embraces bridging divalent alkylradicals such as methylenyl and ethylenyl. The term “lower alkylsubstituted with R²” does not include an acetal moiety.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twelve carbon atoms. Morepreferred alkenyl radicals are “lower alkenyl” radicals having two toabout six carbon atoms. Most preferred lower alkenyl radicals areradicals having two to about four carbon atoms. Examples of alkenylradicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” denotes linear or branched radicals having at leastone carbon-carbon triple bond and having two to about twelve carbonatoms. More preferred alkynyl radicals are “lower alkynyl” radicalshaving two to about six carbon atoms. Most preferred are lower alkynylradicals having two to about four carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for oneexample, may have either an iodo, bromo, chloro or fluoro atom withinthe radical. Dihalo and polyhaloalkyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1-6 carbon atoms. Even morepreferred are lower haloalkyl radicals having one to three carbon atoms.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “hydroxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more hydroxyl radicals. More preferred hydroxyalkyl radicalsare “lower hydroxyalkyl” radicals having one to six carbon atoms and oneor more hydroxyl radicals. Examples of such radicals includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl andhydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals havingone to three carbon atoms.

The term “alkoxy” embrace linear or branched oxy-containing radicalseach having alkyl portions of one to about ten carbon atoms. Morepreferred alkoxy radicals are “lower alkoxy” radicals having one to sixcarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one or two rings wherein such rings may be attachedtogether in a fused manner. The term “aryl” embraces aromatic radicalssuch as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. Morepreferred aryl is phenyl. Said “aryl” group may have 1 to 3 substituentssuch as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy andlower alkylamino. Phenyl substituted with —O—CH₂—O— forms the arylbenzodioxolyl substituent.

The term “heterocyclyl” embraces saturated, partially saturated andunsaturated heteroatom-containing ring radicals, where the heteroatomsmay be selected from nitrogen, sulfur and oxygen. It does not includerings containing —O—O—, —O—S— or —S—S— portions. Said “heterocyclyl”group may have 1 to 3 substituents such as hydroxyl, Boc, halo,haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, aminoand lower alkylamino.

Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of unsaturated heterocyclic radicals, also termed “heteroaryl”radicals, include unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groupcontaining an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, triazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The term also embraces radicals where heterocyclic radicals arefused/condensed with aryl radicals: unsaturated condensed heterocyclicgroup containing 1 to 5 nitrogen atoms, for example, indolyl,isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Preferredheterocyclic radicals include five to ten membered fused or unfusedradicals. More preferred examples of heteroaryl radicals includequinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, triazolyl,oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are5- or 6-membered heteroaryl, containing one or two heteroatoms selectedfrom sulfur, nitrogen and oxygen, selected from thienyl, furyl,pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

Particular examples of non-nitrogen containing heteroaryl includepyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl,benzothienyl, and the like.

Particular examples of partially saturated and saturated heterocyclylinclude pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂).

The term “alkylaminosulfonyl” includes “N-alkylaminosulfonyl” wheresulfamyl radicals are independently substituted with one or two alkylradical(s). More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Even morepreferred are lower alkylaminosulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylaminosulfonyl radicals includeN-methylaminosulfonyl, and N-ethylaminosulfonyl.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” denoteaminocarbonyl radicals independently substituted with one or two alkylradicals, respectively. More preferred are “lower alkylaminocarbonyl”having lower alkyl radicals as described above attached to anaminocarbonyl radical.

The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical.

The term “heterocyclylalkylenyl” embraces heterocyclic-substituted alkylradicals. More preferred heterocyclylalkylenyl radicals are “5- or6-membered heteroarylalkylenyl” radicals having alkyl portions of one tosix carbon atoms and a 5- or 6-membered heteroaryl radical. Even morepreferred are lower heteroarylalkylenyl radicals having alkyl portionsof one to three carbon atoms. Examples include such radicals aspyridylmethyl and thienylmethyl.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferablearalkyl radicals are “lower aralkyl” radicals having aryl radicalsattached to alkyl radicals having one to six carbon atoms. Even morepreferred are “phenylalkylenyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. Even more preferred are lower alkylthio radicals having one tothree carbon atoms. An example of “alkylthio” is methylthio, (CH₃S—).

The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.Even more preferred are lower haloalkylthio radicals having one to threecarbon atoms. An example of “haloalkylthio” is trifluoromethylthio.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”where amino groups are substituted with one alkyl radical and with twoindependent alkyl radicals, respectively. More preferred alkylaminoradicals are “lower alkylamino” radicals having one or two alkylradicals of one to six carbon atoms, attached to a nitrogen atom. Evenmore preferred are lower alkylamino radicals having one to three carbonatoms. Suitable alkylamino radicals may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and thelike.

The term “arylamino” denotes amino groups which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “heteroarylamino” denotes amino groups which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

The term “aralkylamino” denotes amino groups which have been substitutedwith one or two aralkyl radicals. More preferred arephenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino. Thearalkylamino radicals may be further substituted on the aryl ringportion.

The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denoteamino groups which have been substituted with one aralkyl and one alkylradical, or one aryl and one alkyl radical, respectively, to an aminogroup.

The term “aminoalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more amino radicals. More preferred aminoalkyl radicals are“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferredare lower aminoalkyl radicals having one to three carbon atoms.

The term “alkylaminoalkyl” embraces alkyl radicals substituted withalkylamino radicals. More preferred alkylaminoalkyl radicals are “loweralkylaminoalkyl” radicals having alkyl radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkyl radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkylradicals may be mono or dialkyl substituted, such asN-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl andthe like.

The term “alkylaminoalkoxy” embraces alkoxy radicals substituted withalkylamino radicals. More preferred alkylaminoalkoxy radicals are “loweralkylaminoalkoxy” radicals having alkoxy radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkoxy radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyradicals may be mono or dialkyl substituted, such asN-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy andthe like.

The term “alkylaminoalkoxyalkoxy” embraces alkoxy radicals substitutedwith alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxyradicals are “lower alkylaminoalkoxyalkoxy” radicals having alkoxyradicals of one to six carbon atoms. Even more preferred are loweralkylaminoalkoxyalkoxy radicals having alkyl radicals of one to threecarbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono ordialkyl substituted, such as N-methylaminoethoxyethoxy,N,N-dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy and thelike.

The term “carboxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more carboxy radicals. More preferred carboxyalkyl radicalsare “lower carboxyalkyl” radicals having one to six carbon atoms and onecarboxy radical. Examples of such radicals include carboxymethyl,carboxypropyl, and the like. Even more preferred are lower carboxyalkylradicals having one to three CH₂ groups.

The term “halosulfonyl” embraces sulfonyl radicals substituted with ahalogen radical. Examples of such halosulfonyl radicals includechlorosulfonyl and fluorosulfonyl.

The term “arylthio” embraces aryl radicals of six to ten carbon atoms,attached to a divalent sulfur atom. An example of “arylthio” isphenylthio.

The term “aralkylthio” embraces aralkyl radicals as described above,attached to a divalent sulfur atom. More preferred arephenyl-C₁-C₃-alkylthio radicals. An example of “aralkylthio” isbenzylthio.

The term “aryloxy” embraces optionally substituted aryl radicals, asdefined above, attached to an oxygen atom. Examples of such radicalsinclude phenoxy.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. More preferred aralkoxyradicals are “lower aralkoxy” radicals having optionally substitutedphenyl radicals attached to lower alkoxy radical as described above.

The term “heteroaryloxy” embraces optionally substituted heteroarylradicals, as defined above, attached to an oxygen atom.

The term “heteroarylalkoxy” embraces oxy-containing heteroarylalkylradicals attached through an oxygen atom to other radicals. Morepreferred heteroarylalkoxy radicals are “lower heteroarylalkoxy”radicals having optionally substituted heteroaryl radicals attached tolower alkoxy radical as described above.

The term “cycloalkyl” includes saturated carbocyclic groups. Preferredcycloalkyl groups include C₃-C₆ rings. More preferred compounds include,cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Preferred cycloalkenyl groups include C₃-C₆ rings. More preferredcompounds include, for example, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

The phrase “Formula I-XII” includes sub formulas such as II′.

The compounds of the invention are endowed with kinase inhibitoryactivity, such as KDR inhibitory activity.

The present invention also comprises the use of a compound of theinvention, or pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment either acutely orchronically of an angiogenesis mediated disease state, including thosedescribed previously. The compounds of the present invention are usefulin the manufacture of an anti-cancer medicament. The compounds of thepresent invention are also useful in the manufacture of a medicament toattenuate or prevent disorders through inhibition of KDR.

The present invention comprises a pharmaceutical composition comprisinga therapeutically-effective amount of a compound of Formulas I-XII inassociation with a least one pharmaceutically-acceptable carrier,adjuvant or diluent.

The present invention also comprises a method of treating angiogenesisrelated disorders in a subject having or susceptible to such disorder,the method comprising treating the subject with atherapeutically-effective amount of a compound of Formula I

-   wherein each of A¹ and A² is independently C, CH or N;-   wherein ring A is selected from    -   a) 5- or 6-membered partially saturated heterocyclyl,    -   b) 5- or 6-membered heteroaryl,    -   c) 9-, 10- or 11-membered fused partially saturated        heterocyclyl,    -   d) 9-, 10- or 11-membered fused heteroaryl;    -   e) naphthyl, and    -   f) 4-, 5- or 6-membered cycloalkenyl;-   wherein X is

-   wherein Z is oxygen or sulfur;-   wherein Y is selected from

-   wherein p is 0 to 2,-   wherein R^(a) and R^(b) are independently selected from H, halo,    cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R², or wherein R^(a)    and R^(b) together form C₃-C₆ cycloalkyl;-   wherein R^(z) is selected from C₂-C₆-alkylenyl, where one of the CH₂    groups may be replaced with an oxygen atom or an —NH—; wherein one    of the CH₂ groups may be substituted with one or two radicals    selected from halo, cyano, —NHR⁶ and C₁₋₄-alkyl substituted with R²;-   wherein R^(d) is cycloalkyl;-   wherein R is selected from    -   a) substituted or unsubstituted 5-6 membered heterocyclyl, b)        substituted aryl, and    -   c) substituted or unsubstituted fused 9-14-membered bicyclic or        tricyclic heterocyclyl;        -   wherein substituted R is substituted with one or more            substituents independently selected from halo, —OR³, —SR³,            —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³,            —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted            5-6 membered heterocyclyl, optionally substituted phenyl,            nitro, alkylaminoalkoxyalkoxy, cyano, alkylaminoalkoxy,            lower alkyl substituted with R², lower alkenyl substituted            with R², and lower alkynyl substituted with R²;-   wherein R¹ is selected from    -   a) substituted or unsubstituted 6-10 membered aryl,    -   b) substituted or unsubstituted 5-6 membered heterocyclyl,    -   c) substituted or unsubstituted 9-14 membered bicyclic or        tricyclic heterocyclyl,    -   d) cycloalkyl, and    -   e) cycloalkenyl,        -   wherein substituted R¹ is substituted with one or more            substituents independently selected from halo, —OR³, —SR³,            —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄ alkylenylR¹⁴),            —SO₂R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionally            substituted cycloalkyl, optionally substituted 5-6 membered            heterocyclyl, optionally substituted phenyl, halosulfonyl,            cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro,            lower alkyl substituted with R², lower alkenyl substituted            with R², and lower alkynyl substituted with R²;-   wherein R² is one or more substituents independently selected from    H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³,    —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally    substituted phenylalkylenyl, optionally substituted 5-6 membered    heterocyclyl, optionally substituted heteroarylalkylenyl, optionally    substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower    carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl,    lower alkylaminoalkyl and lower haloalkyl;-   wherein R³ is selected from H, lower alkyl, phenyl, heterocyclyl,    C₃-C₆-cycloalkyl, phenylalkyl, heterocyclylalkyl, C₃-C₆    cycloalkylalkyl, and lower haloalkyl;-   wherein R⁴ is selected from a direct bond, C₂₋₄-alkylenyl,    C₂₋₄-alkenylenyl and C₂₋₄-alkynylenyl, where one of the CH₂ groups    may be substituted with an oxygen atom or an —NH—, wherein R⁴ is    optionally substituted with hydroxy;-   wherein R⁵ is selected from H, lower alkyl, phenyl and lower    aralkyl;-   wherein R^(5a) is selected from H, lower alkyl, phenyl and lower    aralkyl;-   wherein R⁶ is selected from H or C₁₋₆-alkyl; and-   wherein R¹⁴ is selected from H, phenyl, 5-6 membered heterocyclyl    and C₃-C₆ cycloalkyl;-   and pharmaceutically acceptable derivatives thereof;    provided A is not naphthyl when X is —C(O)NH— and when R¹ is phenyl    when Y is —NCH₂— and when R is 4-pyridyl; and further provided R is    not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is    —NHCH₂—.

Combinations

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are administered at the same time orsequentially at different times, or the therapeutic agents can be givenas a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of neoplasia, such as withradiation therapy or with cytostatic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formula I may also be administered sequentially with known anticanceror cytotoxic agents when a combination formulation is inappropriate. Theinvention is not limited in the sequence of administration; compounds ofthe invention may be administered either prior to, simultaneous with, orafter administration of the known anticancer or cytotoxic agent.

Currently, standard treatment of primary tumors consists of surgicalexcision followed by either radiation or IV administered chemotherapy.The typical chemotherapy regime consists of either DNA alkylatingagents, DNA intercalating agents, CDK inhibitors, or microtubulepoisons. The chemotherapy doses used are just below the maximaltolerated dose and therefore dose limiting toxicities typically include,nausea, vomiting, diarrhea, hair loss, neutropenia and the like.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents.

A first family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine,anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from but not limited to the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRIInternational NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from but not limited to thegroup consisting of α-carotene, α-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluoron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin,elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine,etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate,genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives,methylanilinoacridine, Molecular Genetics MGI-136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM-534.

Alternatively, the present compounds may also be used in co-therapieswith other anti-neoplastic agents, such as acemannan, aclarubicin,aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine,aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole,ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos),bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin,cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030(Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane,dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine,doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HITdiclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin,edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetinbeta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim,finasteride, fludarabine phosphate, formestane, fotemustine, galliumnitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafurcombination, glycopine, goserelin, heptaplatin, human chorionicgonadotropin, human fetal alpha fetoprotein, ibandronic acid,idarubicin, (imiquimod, interferon alfa, interferon alfa, natural,interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferonalfa-N1, interferon alfa-n3, interferon alfacon-1, interferon alpha,natural, interferon beta, interferon beta-1a, interferon beta-1b,interferon gamma, natural interferon gamma-1a, interferon gamma-1b,interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole,leukocyte alpha interferon, leuprorelin, levamisole+fluorouracil,liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol,metoclopramide, mifepristone, miltefosine, mirimostim, mismatched doublestranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim,nafarelin, naloxone+pentazocine, nartograstim, nedaplatin, nilutamide,noscapine, novel erythropoiesis stimulating protein, NSC 631570octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronicacid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium,pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonalantibody, polyethylene glycol interferon alfa-2a, porfimer sodium,raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RIIretinamide, rituximab, romurtide, samarium (153 Sm) lexidronam,sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride,suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide,teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropinalfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab,treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumornecrosis factor alpha, natural, ubenimex, bladder cancer vaccine,Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin,vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid;abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide,bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine,dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche),eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen),fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy(Vical), granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

Alternatively, the present compounds may also be used in co-therapieswith other anti-neoplastic agents, such as other kinase inhibitorsincluding p38 inhibitors and CDK inhibitors, TNF inhibitors,metallomatrix proteases inhibitors (MMP), COX-2 inhibitors includingcelecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's,SOD mimics or α_(v)β₃ inhibitors.

The present invention comprises processes for the preparation of acompound of Formula I-XII.

Also included in the family of compounds of Formula I-XII are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I-XII may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, adipic, butyric, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic,pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaI-XII include metallic salts, such as salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc, or salts made fromorganic bases including primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, trimethylamine. All of these salts may be prepared byconventional means from the corresponding compound of the invention byreacting, for example, the appropriate acid or base with the compound ofFormula I-XII.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.Preferred salts include hydrochloride, phosphate and edisylate.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66, 1 (1977).

General Synthetic Procedures

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes 1-48, wherein the substituents are asdefined for Formulas I-XII, above, except where further noted.

Cyclic amides can be prepared according to the method set out inScheme 1. The amino group of compound 1 (where R^(o) is alkyl, aryl, andthe like) is protected, such as with Boc anhydride, followed bytreatment, to remove the ester, such as with base, forming the protectedamine/free acid 2. Alternatively, other amino protecting groups known inthe art can be used. Substituted amines are coupled with the free acid,such as with EDC, to form the protected amine/amide 3. The protectedamine moiety is deprotected, such as with acid, and reacted via one stepreductive alkylation with carbonyl-containing compounds (where R′ is H,halo, cyano, —NHR⁶ and C₁₋₄ alkyl) to form the 1-amido-2-substitutedamino-compounds 4. Preferably the amination is in an alcohol, such asMeOH, EtOH or propanol, and at a temperature between about 0-50° C.,such as RT. Aldehydes or ketones are preferred carbonyl-containingcompounds. Alternative carbonyl-containing compounds are, for example,bisulfite adducts or hemiacetals, acetals, hemiketals or ketals ofcompounds with alcohols, for example lower hydroxyalkyl compounds; orthioacetals or thioketals of compounds with mercaptans, for examplelower alkylthio compounds. The reductive alkylation is preferablycarried out with hydrogenation in the presence of a catalyst, such asplatinum or especially palladium, which is preferably bonded to acarrier material, such as carbon, or a heavy metal catalyst, such asRaney nickel, at normal pressure or at pressures of from 0.1 to 10MegaPascal (MPa), or with reduction by means of complex hydrides, suchas borohydrides, especially alkali metal cyanoborohydrides, for examplesodium cyanoborohydride, in the presence of a suitable acid, preferablyrelatively weak acids, such as lower alkylcarboxylic acids, especiallyacetic acid, or a sulfonic acid, such as p-toluenesulfonic acid; incustomary solvents, for example alcohols, such as MeOH or EtOH, orethers, for example cyclic ethers, such as THF, in the presence orabsence of water.

Alternatively, compounds 4 can be prepared from mixed acid/amines 5 asshown in Scheme 2. Substituted amines are coupled with the mixedacid/amines 5 such as with a coupling reagent, for example EDC, to formthe mixed amine/amide 6. Substituted carbonyl compounds, such as acidhalides, anhydrides, carboxylic acids, esters, ketones, aldehydes andthe like, are added to the mixed amine/amide 6 followed with reductionto give the substituted amide/substituted amine compounds 4.

Imino compounds 7 can be formed from the mixed amine/amides 6, such asby reacting with a substituted carbonyl compound.

Substituted cyclic carboxamides can be prepared from the correspondingimino analogs by the process outlined in Scheme 4. Treatment of theimino compound 7 with a reducing agent yields compound 4. Reagents whichcan be used to add hydrogen to an imine double bond include borane inTHF, LiAlH₄, NaBH₄, sodium in EtOH and hydrogen in the presence of acatalyst, and others.

Substituted carboxamides 4 can be prepared from the corresponding haloanalogs 8 by the process outlined in Scheme 5. Substituted amino acids 9are prepared from the corresponding chloro compounds 8 such as byreacting with an amine at a suitable temperature, such as about 80° C.The acid 9 is coupled with an amine, preferably in the presence of acoupling agent such as EDC, to form the corresponding amide 4.

The amination process can be carried out as an Ullmann type reactionusing a copper catalyst, such as copper[0] or a copper[I] compound suchas copper[I]oxide, copper[I]bromide or copper[I]iodide in the presenceof a suitable base (such as a metal carbonate, for example K₂CO₃) toneutralize the acid generated in the reaction. This reaction is reviewedin Houben-Weyl “Methoden der Organischen Chemie”, Band 11/1, page 32-33,1958, in Organic Reactions, 14, page 19-24, 1965 and by J. Lindley(1984) in Tetrahedron, 40, page 1433-1456. The amount of catalyst istypically in the range of 1 to 20 mole percent. The reaction is carriedout in an inert, aprotic solvent such as an ether (for exampledimethoxyethane or dioxane) or an amide (for example dimethylformamideor N-methylpyrrolidone), under an inert atmosphere in the temperaturerange of 60-180° C.

An alternative amination process involves using a Group VIII element,where the metal core of the catalyst should be a zero-valent transitionmetal, such as palladium or nickel, which has the ability to undergooxidative addition to the aryl-halogen bond. The zero valent state ofthe metal may be generated in situ from the M[II] state. The catalystcomplexes may include chelating ligands, such as alkyl, aryl orheteroaryl derivatives of phosphines or biphosphines, imines or arsines.Preferred catalysts contain palladium or nickel. Examples of suchcatalysts include palladium[II]chloride, palladium[II]acetate,tetrakis(triphenyl-phosphine)palladium[0] and nickel[II]acetylacetonate.The metal catalyst is typically in the range of 0.1 to 10 mole percent.The chelating ligands may be either monodentate, as in the case forexample of trialkyphosphines, such as tributylphosphine,triarylphosphines, such as tri-(ortho-tolyl)phosphine, and triheteroarylphosphines, such as tri-2-furylphosphine; or they may be bidentate suchas in the case of 2,2′-bis(diphenylphosphino)-1,1′binaphthyl,1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferroceneand 1-(N,N-dimethyl-amino)-1′-(dicyclohexylphosphino)biphenyl. Thesupporting ligand may be complexed to the metal center in the form of ametal complex prior to being added to the reaction mixture or may beadded to the reaction mixture as a separate compound. The supportingligand is typically present in the range 0.01 to 20 mole percent. It isoften necessary to add a suitable base to the reaction mixture, such asa trialkylamine (for example DIEA or1,5-diazabicyclo[5,4,O]undec-5-ene), a Group I alkali metal alkoxide(for example potassium tert-butoxide) or carbonate (for example cesiumcarbonate) or potassium phosphate. The reaction is typically carried outin an inert aprotic solvent such as an ether (for exampledimethoxyethane or dioxane) or an amide (for example, DMF orN-methylpyrrolidone), under an inert atmosphere in the temperature rangeof 60-180° C.

The amination is preferably carried out in an inert, aprotic, preferablyanhydrous, solvent or solvent mixture, for example in a carboxylic acidamide, for example DMF or dimethylacetamide, a cyclic ether, for exampleTHF or dioxane, or a nitrile, for example CH₃CN, or in a mixturethereof, at an appropriate temperature, for example in a temperaturerange of from about 40° C. to about 180° C., and if necessary under aninert gas atmosphere, for example a nitrogen or argon atmosphere.

Substituted carboxamides 4 can be prepared from the corresponding haloanalogs 8 by the process outlined in Scheme 6. The chloro acid 8 iscoupled with an amine, preferably in the presence of a coupling agentsuch as EDC, to form the corresponding chloro amide 10. Substitutedamino-amides 4 are prepared from the corresponding chloro compounds 10such as by reacting with an amine at a suitable temperature, such asabout 80° C. The amination reaction can be run in the presence of anappropriate catalyst such as a palladium catalyst, in the presence of anaprotic base such as sodium t-butoxide or cesium carbonate, or a nickelcatalyst, or a copper catalyst.

Substituted carboxamides 4 can be prepared from the correspondingbromo/chloro analogs 11 by the process outlined in Scheme 7. Thebromo/chloro acid 11 is coupled with an amine, preferably in thepresence of a coupling agent such as EDC, to form the correspondingbromo substituted amide 12. Suzuki coupling with the bromo amide 12 andsuitable boronic acids provides the substituted amide 10. Substitutedamino-amides 4 are prepared from the corresponding chloro compounds 10as described in Scheme 6.

Substituted thiophenes 16 can be prepared by the method of Scheme 8. Thefree amino group of a 3-amino-2-thiophenecarboxylic acid ester 13 can beprotected such as by the addition of Boc₂O in a suitable solvent such asCH₂Cl₂ and DMAP. The ester is removed such as with base to form the freeacid 14. The thiophene amide 15 is formed from the acid 14 such as bycoupling with a substituted amine in the presence of DIEA, EDC and HOBt.The 2-protected-amino-thiophene amide 15 is deprotected, such as with25% TFA/CH₂Cl₂. The free amine is alkylated such as with a substitutedcarboxaldehyde or similar active carbonyl compound, in the presence of areducing agent NaCNBH₃ and the like, to form compounds 16.

Substituted pyridines can be prepared such as by the method found inScheme 9. 2-Aminonicotinic acid 17 is coupled with a substituted amineat a suitable temperature, nonprotic solvent such as CH₂Cl₂, such aswith EDC and HOBt, to form the nicotinamide 18. The nicotinamide 18 isreductively alkylated such as with 4-pyridinecarboxaldehyde andNaBH(OAc)₃, to yield the 2-substituted amino-pyridyl carboxamides 19.

Substituted pyridines may be prepared by the method found in Scheme 10.2-Chloro-nicotinic acid 20 is coupled with an amine 21 at a suitabletemperature, such as a temperature over about 100° C. to give the2-substituted amino-nicotinic acid 22. The 2-substituted amino-nicotinicacid 22 is reacted with a substituted amine in the presence of acoupling reagent, such as BOP-Cl and base, such as TEA to form the2-substituted amino-nicotinamide 19.

Alternatively, 2-chloro-nicotinoyl chloride (LG is Cl) is coupled firstwith R¹—NH₂ such as in the presence of base, e.g., NaHCO₃, in a suitablesolvent, such as CH₂Cl₂, to form the amide 20A, then coupling with apyridylmethylamine to yield the 2-substituted amino-nicotinamide 19.

Imino-substituted pyridines may be prepared by the method found inScheme 11. (2-Amino-(4-pyridyl))-carboxamide 23 is reacted with4-pyridine-carboxaldehyde, such as in the presence of p-toluenesulfonicacid monohydrate to yield the imino compound 24.

Substituted pyridines alternatively may be prepared by the method foundin Scheme 12. The imino compound 24 is reduced, such as with NaBH₄, toform the substituted amine 25.

Substituted pyridines can be prepared by the process outlined in Scheme13. A solution of sodium hypobromide is freshly prepared and added to2-hydroxynicotinic acid 26 and heated, preferably at a temperature atabout 50° C. Additional sodium hypobromide may be needed to form thebromo compound 27. The 5-bromo-2-hydroxynicotinic acid 27 is reactedwith thionyl chloride, preferably at a temperature >RT, more preferablyat about 80° C. to form the 2-chloro-nicotinic acid analog 28. The acidis coupled with an amine, preferably in the presence of EDC, HOBT, andDIEA to form the corresponding substituted amide 29. Suzuki couplingwith the bromo amide and suitable boronic acids, provides thesubstituted nicotinamide 30. 2-Amino-nicotinamides 31 are prepared fromthe corresponding chloro compounds 30 such as by reacting withsubstituted amines at a suitable temperature, such as about 80° C.

Sulfonamides 32 can be prepared from amines 6 as shown in Scheme 14.Substituted sulfonyl compounds, such as sulfonyl halides, preferablychloro or bromo, sulfonic acids, an activated ester or reactiveanhydride, or in the form of a cyclic amide, and the like, are added tothe amine 6 to give the sulfonamide compounds 32.

The reaction is carried out in a suitable solvent, such as CH₂Cl₂, at atemperature between about RT to about the reflux temperature of thesolvent, in the presence of a suitable base, such as DIEA or DMAP.

The amino group of compounds 6 is preferably in free form, especiallywhen the sulfonyl group reacting therewith is present in reactive form.The amino group may, however, itself be a derivative, for example byreaction with a phosphite, such as diethylchlorophosphite, 1,2-phenylenechlorophosphite, ethyldichlorophosphite, ethylene chlorophosphite ortetraethylpyrophosphite. A derivative of such a compound having an aminogroup also can be a carbamic acid halide or an isocyanate.

The condensation of activated sulfonic esters, reactive anhydrides orreactive cyclic amides with the corresponding amines is customarilycarried out in the presence of an inorganic base, such as an alkalinemetal hydrogen carbonate of carbonate, or especially an organic base,for example simple lower (alkyl)-3-amines, for example TEA ortributylamine, or one of the above-mentioned organic bases. If desired,a condensation agent is additionally used, for example as described forfree carboxylic acids.

The condensation is preferably carried out in an inert, aprotic,preferably anhydrous, solvent or solvent mixture, for example in acarboxylic acid amide, for example formamide or DMF, a halogenatedhydrocarbon, for example CH₂Cl₂, CCl₄ or chlorobenzene, a ketone, forexample acetone, a cyclic ether, for example THF or dioxane, an ester,for example EtOAc, or a nitrile, for example CH₃CN, or in a mixturethereof, as appropriate at reduced or elevated temperature, for examplein a temperature range of from about −40° C. to about +100° C.,preferably from about −10° C. to about 70° C., and when arylsulfonylesters are used, also at temperatures of from about 10-30° C., and ifnecessary under an inert gas atmosphere, for example a nitrogen or argonatmosphere.

Alcoholic solvents, for example EtOH, or aromatic solvents, for examplebenzene or toluene, may also be used. When alkali metal hydroxides arepresent as bases, acetone may also be added where appropriate.

Substituted pyridines can be prepared by the process outlined in Scheme15. 2-Chloronicotinic acid 33 and substituted amine are coupled underconditions similar to that described in the previous schemes to give theamide 34. 6-Chloro-2-aminopyridines 35 are prepared from the amide 34,such as by reacting with substituted amines at a suitable temperature,such as above about 80° C., preferably above about 100° C., morepreferably at about 130° C., neat. 6-Chloro-2-aminopyridines 35 arede-chlorinated such as by hydrogenation, for example by treatment withH₂ in the presence of Pd/C, to yield other compounds of the presentinvention 36.

1,2,3,6-Tetrahydro-pyridyl substituted anilines are prepared such as bythe procedure described in Scheme 16 (where R^(x) is a substituentselected from those available for substituted R¹). Nitrobenzenes 37 arebrominated, such as with bromine in the presence of acid, H₂SO₄ forexample, or with NBS to yield the 3-bromo derivative 38. Suzuki couplingof the bromo-derivative 38 and a substituted pyridylboronic acid, in anappropriate solvent such as toluene, such as at a temperature above RT,preferably above about 50° C., and more preferably at about 80° C.,yields the pyridyl derivative 39. Alkylation of the nitrophenyl-pyridine39, such as by treatment with iodomethane, preferably above about 50°C., and more preferably at about 80° C., yields the pyridinium compound40, which upon reduction, such as by NaBH₄, yields thetetrahydropyridine 41.

6-Amino substituted pyridines are prepared such as by the proceduredescribed in Scheme 17. Similar to the method of Scheme 13,chloropyridine 42 and is reacted with an amine, preferably above about50° C., and more preferably at about 80° C., to yield the6-aminopyridines 43.

A series of substituted anilines are prepared such as by the proceduredescribed in Scheme 18. A nitrobenzyl bromide 44 is coupled withmorpholine, such as at a temperature at about RT, to yield theheterocyclylmethyl nitrobenzene derivative. Reduction of the nitrocompound, such as with iron powder, preferably above about 50° C., andmore preferably at about 80° C., yields the heterocyclylmethylsubstituted aniline 45.

Protected alkylamine substituted anilines can be prepared from the nitrofree amines 46, such as with standard protecting agents and chemistryknown in the art, such as BOC chemistry. Reduction of the protectednitro compound, such as with iron powder, preferably above about 50° C.,and more preferably at about 80° C., yields the aniline 47.

Sulfonamide substituted anilines can be prepared fromnitrobenzenesulfonyl chlorides 48. Coupling of nitrobenzenesulfonylchlorides 48 with reactive heterocyclic compounds, such as substitutedpiperazines, piperidines, and the like, in a protic solvent such asEtOH, such as at a temperature about RT, yields thenitrobenzenesulfonamides 48. Reduction of the nitro benzenesulfonamide,such as with iron powder, preferably above about 50° C., and morepreferably at about 80° C., yields the aniline 49.

A series of perhaloalkyl-substituted anilines 52, where R^(y) representsperhaloalkyl radicals, are prepared such as by the procedure describedin Scheme 19. 1-Nitro-4-(perfluoroethyl)benzene can be synthesized bythe method described in the reference [John N. Freskos, SyntheticCommunications, 18(9), 965-972 (1988)]. Alternatively,1-Nitro-4-(perfluoroalkyl)benzene can be synthesized from the nitrocompound, where X^(a) is a leaving group, such as iodo, by the methoddescribed by W. A. Gregory, et al. [J. Med. Chem., 1990, 33, 2569-2578].

Reduction of the nitrobenzenes 51, such as with iron powder, at atemperature above about 50° C., and preferably at about 80° C., yieldsthe aniline 52. Hydrogenation, such as with H₂ in the presence ofcatalyst, such as Pd/C, is also possible.

Additional series of substituted anilines are prepared such as by theprocedures described in Scheme 20 (where R^(x) is a substituent selectedfrom those available for substituted R¹). 2-Alkoxy substituted anilines55 are prepared from the corresponding phenol compounds 53 such as bythe Mitsunobu reaction, including treatment with aN,N-dialkylethanolamine and PPh₃ and DEAD to give the correspondingnitro compound 54, followed by hydrogenation, such as with H₂ to givethe aniline 55.

Alternatively, piperazinyl substituted anilines 58 can be prepared bythe treatment of an aniline 56 with anN-substituted-bis(2-chloroethyl)amine, base, such as K₂CO₃ and NaI, at atemperature above about 50° C., preferably above about 100° C., and morepreferably at about 170° C., to give the piperazinylbenzene compound 57.Nitration, such as with H₂SO₄ and HNO₃, at a temperature above 0° C.,and preferably at about RT, followed by hydrogenation, such as with H₂atmosphere gives the substituted aniline 58.

Alternatively, piperazinyl substituted anilines 61 can be prepared bythe treatment of a fluoro-nitro-substituted aryl compounds 59. Thefluoro-nitro-substituted aryl compounds 59 and 1-substituted piperazinesare heated, preferably neat, at a temperature above about 50° C., andpreferably at about 90° C., to yield the piperazinyl-nitroaryl compounds60. Hydrogenation, such as with H₂ atmosphere in the presence of acatalyst, such as 10% Pd/C, gives the substituted aniline 61.

Substituted indolines are prepared such as by the procedures describedin Scheme 21. Substituted amino-indolines 64 are prepared from thenitroindoline 62 and a ketone in the presence of NaHB(OAc)₃ to form the1-substituted indoline 63. The nitroindoline 63 is hydrogenated, such aswith H₂ in the presence of a catalyst, such as Pd/C, to yield theamino-indoline 64.

Alternatively, substituted amino-indolines 67 are prepared from thenitroindoline 62. Nitroindoline 62, is reacted with an acid chloride toform an amide. Further treatment with a primary or secondary amine,preferably a secondary amine, such as in the presence of NaI, at atemperature above about 50° C., and preferably at about 70° C. yieldsthe nitroindoline 65. The nitro compound 65 is hydrogenated, such aswith H₂ in the presence of a catalyst, such as Pd/C, to yield theamino-indoline 66. The carbonyl is reduced, such as with BH₃-THF yields1-aminoalkyl-indolines 67.

Substituted indolines are prepared such as by the procedures describedin Scheme 22. Substituted acetamides 69 are prepared from the acylationof halo-5-nitroanilines 68 (where LG is bromo or chloro, preferablychloro) with an acylating agent, such as acetyl chloride or aceticanhydride, under standard coupling chemistry, such as with DIEA, andDMAP, at a temperature of about RT, in a suitable solvent, such asCH₂Cl₂, DMF and/or DMAC. The N-(2-methylprop-2-enyl)acetamide 70 isprepared from the acetamide 69, such as by the treatment of base, suchas NaH in anhydrous DMF and a 3-halo-2-methylpropene such as3-bromo-2-methylpropene or 3-chloro-2-methylpropene, at a temperaturebetween about 0° C. and RT, and preferably at about RT; or with CsCO₂ ata temperature above RT, preferably above about 50° C. and morepreferably above about 60° C. Cyclization of theN-(2-methylprop-2-enyl)acetamide 70, such as by the Heck-type reaction(treatment with Pd(OAc)₂ in the presence of base, for exampletetraethyl-ammonium chloride, sodium formate, and NaOAc) at atemperature above about 50° C., and preferably at about 80° C., yieldsthe protected (3,3-dimethyl-2,3-dihydro-indol-1-yl)ethanone 71.Deprotection, such as with strong acid such as AcOH on HCl at atemperature above about 50° C., and preferably at about 70-80° C.,yields the 3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl 72.Alternatively, the protected dihydro-6-nitro indoline 71 can be reduced,such as with Fe, or with 10% Pd/C in the presence of an excess ofNH₄CO₂H, or with H₂ in the presence of a catalyst to form the protecteddihydro-6-amino indoline 71a.

Substituted anilines are prepared such as by the procedures described inScheme 23. Nitrophenyl esters 74 are formed from the acid 73, such as bytreatment with MeOH and acid. Alkylation of the ester 74, such as bytreatment with base, followed by alkyl halide, yields the branched alkylcompounds 75. Reduction of the ester 75, such as with BH₃, yields thealcohol 76. The aldehyde 77 is prepared from the alcohol 76, such as bytreatment with TPAP in the presence of N-methylmorpholine-N-oxide.Subsequent treatment with methoxymethyltriphenylphosphonium chloride andKHMDS yields 77. Coupling of the aldehyde 77 with morpholine, such aswith NaBH(OAc)₃ yields the tertiary amine 78. Reduction of the nitrocompound, such as with acid, for example AcOH, and zinc yields theaniline 79.

Substituted aminomethyl compounds are prepared such as by the proceduredescribed in Scheme 24. A piperidinemethanol 80 is reacted withformaldehyde and NaCNBH₃. Subsequently, base, such as sodium hydride,and a halo substituted cyclic nitrile gives the ether 81. Hydrogenationof 81 under conditions described above, furnishes the aminomethylcompound 82.

Substituted aniline compounds are prepared such as by the proceduredescribed in Scheme 25 (where R^(x) is a substituent selected from thoseavailable for substituted R¹, preferably haloalkyl or alkyl).Alkynyl-aniline 84, prepared similar to that described in Scheme 46, ishydrogenated such as with H₂ in the presence of a catalyst, such asPd(OH)₂, to yield the substituted alkyl 85.

Substituted bromophenyl compounds are prepared such as by the proceduredescribed in Scheme 26. Bromine is added to a optionally substitutednitrobenzene 86, silver(II)sulfate and acid, such as H₂SO₄, to providethe bromo derivative 87.

Substituted anilines are prepared such as by the procedure described inScheme 27 (where R^(t) and R^(v) are alkyl, or together with thenitrogen atom form a 4-6 membered heterocyclic ring). Acryloyl chloride88 is reacted with an amine, preferably a secondary amine, such as at atemperature between about 0° C. and about RT, to form the amide 89. Abromo-nitrobenzene 87 is reacted with the amide 89, such as in thepresence of base, for example TEA, together with Pd(OAc)₂ and Pd(PPh₃)₄,at a temperature above about 50° C., and preferably at about 120° C.,such as in a sealed container, to form the substituted alkene 90.Hydrogenation of the alkene 90, such as with H₂-in the presence of acatalyst, for example Pd/C catalyst yields the substituted aniline 91.Reduction of the amide 91, such as with LiAlH₄, at a temperature aboveabout 50° C., and preferably at about 80° C. yields the aniline 92.

Substituted indoles are prepared such as by the procedure described inScheme 28. A nitroindole 93 is coupled with a halo compound, in thepresence of base, for example K₂CO₃. Heating at a temperature aboveabout 50° C., and preferably at about reflux yields thesubstituted-nitro-1H-indole 94. Hydrogenation similar to conditionsdescribed above yield the amino derivative 95.

Substituted pyrimidines are prepared such as by the procedure describedin Scheme 29. 2-Methylthio-5-pyrimidyl acids 98 are prepared from thecorresponding esters 96 similar to procedures described above. Theamides 99 are formed from the acids 98 by coupling with the amine suchas in the presence of HATU and base, TEA for example. The methylthiogroup can be removed, such as with Raney-Ni and heat, preferably atabout reflux temperature, to form the pyrimidine 100.

Substituted aminomethyl compounds are prepared such as by the proceduredescribed in Scheme 30 (where LG is a leaving group, such as Cl). Strongbase, such as NaH is added to an alcohol and heated at about 50° C. toform the sodium alkoxide, which is added to a halo compound, such as2-chloro-4-cyanopyridine and heated at a temperature above about 50° C.,and preferably at about 70° C. to form the ether 102. Hydrogenationyields the aminomethyl derivative 103.

Substituted anilines are prepared such as by the procedure described inScheme 31. Treatment with the haloalkyl alcohol 104 with an alcohol,such as in the presence of DEAD and PPh₃ yields the ether 105 or 106.

Functionalized pyridines are prepared such as by the procedure describedin Scheme 32. 2-Fluoropyridine 107 is treated with base, such as LDA ata temperature below about 0° C., and preferably at about −78° C., andquenched with a stream of dry CO₂ to form the nicotinic acid 108.Alternatively, solid CO₂ (dry ice) can be used, preferably dried with N₂prior to use. The acid 108 is converted to the acid halide 109, such asby treatment with thionyl chloride and heating at a temperature aboveabout 50° C., and preferably at about reflux.

Chloro-substituted pyridines 110 are prepared such as by the proceduredescribed in Scheme 33. 2-Chloronicotinic acid is activated with ethylchloroformate, in the presence of base, such as TEA, at a temperature ofabout RT. Reaction with an amine produces amide 110. Alternatively, theamine can be coupled with the acid chloride 111, such as withpolymer-supported DIPEA, to form amide 110. Excess acid chloride isremoved by treating the reaction mixture with polymer-supportedtrisamine resin.

Amino-substituted indoles 110 are prepared such as by the proceduredescribed in Scheme 34. Nitroindoline 112 is reacted withN-methyl-4-piperidone in the presence of NaOMe at a temperature aboveabout 50° C., and preferably at about reflux, to form the 3-substitutedindole 113. Hydrogenation as previously discussed yields the aminoindole 114.

Alkylated indazoles can be prepared by the process outlined in Scheme35. To a solution of 6-nitroindazole 115 in a solvent such as THF isadded strong base, such as NaH at a temperature below RT, preferably atabout 0° C. Alkylhalides, such as where R″ is methyl, are added andreacted at a temperature about RT to give 1-alkyl-6-nitro-1H-indazole116. The nitro indazole 116 is hydrogenated, such as with an H₂atmosphere in the presence of a catalyst, such as Pd/C to give the1-substituted-6-amino-1H-indazole 117.

Brominated indazoles can be prepared by the process outlined in Scheme36. NBS is slowly added to an acidic solution, such as a mixture ofTFA:H₂SO₄ (5:1) and tert-butyl-4-nitrobenzene 118 at a temperature ofabout RT to yield the brominated compound 119.

Substituted anilines can be prepared by the process outlined in Scheme38. A mixture of 1-(substituted)-2-bromo-4-nitrobenzene 120 (where R^(x)is a substituent selected from those available for substituted R¹) andN-methylpiperazine is heated, such as with or without solvent,preferably without solvent, at a temperature above RT, preferably at atemperature above about 100° C., and more preferably at a temperature atabout 130° C. to give the1-[5-(substituted)-2-nitrophenyl]-4-methylpiperazine 121. The nitrocompound 121 is hydrogenated, such as with an H₂ atmosphere in thepresence of a catalyst, such as Pd/C to furnish4-(substituted)-2-(4-methylpiperazinyl)phenylamine 122.

Tricyclic heterocycles can be prepared by the process outlined in Scheme38. 7-Nitro-2,3,4-trihydroisoquinolin-1-one 123 is heated in POCl₃ at atemperature above RT, preferably at a temperature sufficient for reflux,to form the 1-chloro-7-nitro-3,4-dihydroisoquinoline 124. The1-chloro-7-nitro-3,4-dihydroisoquinoline 124 is dissolved in a solvent,such as THF, and H₂NNH₂ is added. The reaction is evaporated to aresidue, then heated with HC(OEt)₃ at a temperature above RT, preferablyat a temperature above about 75° C., and more preferably at atemperature at about 115° C. to give the nitro-substituted tricyclic.Hydrogenation, such as with an H₂ atmosphere in the presence of acatalyst, such as Pd/C, gives2-amino-5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline 125.

Indazolyl ethers can be prepared by the process outlined in Scheme 39.6-Nitro-1H-2-hydroindazol-3-one 126 is protected such as with Boc₂O andDMAP in CH₂Cl₂ at a temperature of about RT, to give the protected6-nitro-2-hydroindazol-3-one. The protected 6-nitro-2-hydroindazol-3-oneis reacted with an alcohol (where R^(x) is an appropriate substituentselected from the possible substituents on R) and Ph₃P in a solvent,such as THF, and DEAD, at a temperature of about RT, to give theprotected 6-nitro(indazol-3-yl)ether. The nitro intermediate ishydrogenated, such as with an H₂ atmosphere in the presence of acatalyst, such as Pd/C, to give the protected 6-amino(indazol-3-yl)ether127. The amine 127 is coupled and 2-chloronicotinic acid in a solvent,such as an alcohol, preferably pentanol, at a temperature above RT,preferably at a temperature above about 75° C., and more preferably at atemperature at about 130° C. to give the coupled and deprotectedcompound 128.

Indolinyl substituted carboxamides can be prepared from thecorresponding nitro indoline 129 by the process outlined in Scheme 40.For example, 3,3-dimethyl-6-nitroindoline 129 is alkylated, such as withN-protected-4-formylpiperidine in the presence of NaHB(OAc)₃ and acid,such as glacial AcOH, and solvent, such as dichloromethane, at atemperature of about RT, to afford the alkylated indane 130.Hydrogenation of the alkylated indane 130, such as with an H₂ atmospherein the presence of a catalyst, such as Pd/C, in the presence of asolvent, such as an alcohol, preferably MeOH, to give the aminointermediate 131. Alternatively, other hydrogenation methods can beused, such as Fe powder with NH₄Cl. Coupling of the amine 131, such aswith 2-chloronicotinic acid and DIEA, HOBt and EDC, in a solvent such asCH₂Cl₂ at a temperature of about RT provides the protected carboxamide132, which upon deprotection and alkylation yields other compounds ofthe invention, 133 and 134, respectively. Alternatively, amine 131 isreacted with 2-fluoronicotinoyl chloride to form a 2-fluoronicotinamide,which can be alkylated, such as in Scheme 10.

Substituted anilines can be prepared by the process outlined in Scheme41. 1-Methyl-4-piperidinone 135 is added to a solution of strong basesuch as LiHMDS, in a solvent such as THF, at a temperature below RT,preferably lower than about −50° C., more preferably at about −78° C.Tf₂NPh is reacted with the enolate at a temperature of about RT, to give1-methyl-4-(1,2,5,6-tetrahydro)pyridyl-(trifluoromethyl)sulfonate. Amixture of the triflate intermediate, bis(pinacolato)diboron, potassiumacetate, PdCl₂dppf, and dppf in a solvent such as dioxane is heated at atemperature above RT, preferably at a temperature above about 50° C.,and more preferably at a temperature at about 80° C. to give4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane136. The substituted aniline 137 is formed from the 1,3,2-dioxaborolane136 such as with treatment with an amine in the presence of1,1′-bis(diphenyphosphino)ferrocene-palladium dichloride and base, suchas K₂CO₃, in a solvent such as DMF at a temperature above RT, preferablyat a temperature above about 50° C., and more preferably at atemperature at about 80° C.

Substituted anilines can be prepared by the process outlined in Scheme42. 4-Cyano-4-phenylpiperidine hydrochloride 138 is treated with base,such as KOH, at a temperature above RT, preferably at a temperatureabove about 100° C., and more preferably at a temperature at about 160°C., to provide the phenyl piperidine 139. Alkylation of the phenylpiperidine 139, such as with formaldehyde and NaCNBH₃ in a solvent suchas CH₃CN, with sufficient acid to maintain the reaction pH near 7, toprovide the alkylated piperidine 140. Nitration of the phenylpiperidine140, such as with H₂SO₄ and fuming HNO₃ at a temperature below RT, andpreferably at about 0° C., gives the nitro intermediate 141.Hydrogenation of the nitro intermediate 141, such as with an H₂atmosphere in the presence of a catalyst, such as Pd/C, in the presenceof a solvent, such as an alcohol, preferably MeOH, to give the aminointermediate 142.

Substituted amides can be prepared by the process outlined in Scheme 43.3-Nitrocinnamic acid 143 is coupled with 1-methylpiperazine in thepresence of EDC and a solvent such as CH₂Cl₂, at a temperature of aboutRT gives the carboxamide 144.

Substituted benzylamines can be prepared by the process outlined inScheme 44. A substituted bromobenzylamine 145 where R^(1a) is asubstituent described for R¹ is protected such as with Boc₂O in thepresence of base, such as TEA in an appropriate solvent such as CH₂Cl₂.The protected bromobenzylamine 146 is alkylated, such as with1-dimethylamino-2-propyne in the presence of catalyst, such asPdCl₂(PPh₃)₂, and CuI, in the presence of base, such as TEA, at atemperature above RT, preferably at a temperature above about 50° C.,and more preferably at a temperature at about 100° C., such as in asealed tube, to form the propynylbenzylamine 147. Thepropynylbenzylamine is hydrogenated such as with H₂ in the presence ofPd(OH)₂ and MeOH to provide the propylbenzylamine 148. Deprotection,such as with strong acid, such as TFA, for removal of a Boc protectinggroup, yields the propylbenzylamine 149.

Substituted benzylamines can be prepared by the process outlined inScheme 45. The protected bromobenzylamine 146 is alkylated, such as withpropargyl alcohol in the presence of catalyst, such as PdCl₂(PPh₃), andCuI, in the presence of base, such as TEA, at a temperature above RT,preferably at a temperature above about 50° C., and more preferably at atemperature at about 100° C., such as in a sealed tube, to form theprotected hydroxypropynylbenzylamine 150. The protectedhydroxypropynylbenzylamine is treated with N-methylmorpholine oxide inthe presence of a catalyst, such as tetrapropylammonium perruthenate, toform the aldehyde intermediate. Reductive amination, such as with theaddition of morpholine and NaBH(OAc)₃ provides the morpholinylderivative. Deprotection, such as with strong acid, such as TFA, forremoval of a Boc protecting group, yields the propylbenzylamine 151.

Substituted aminomethyl compounds are prepared such as by the proceduredescribed in Scheme 46. A halo compound 152, is reacted with an alkynein the presence of PdCl₂(PPh₃)₂ and CuI, with base is heated at atemperature above about 50° C., and preferably at about 100° C., such asin a sealed container, to provide the substituted alkyne 153.

Substituted heterocycles may be prepared by the method found in Scheme47. Chloro-heterocycles 154 (where LG is OH) is coupled with an amine155 at a suitable temperature, such as a temperature over about 100° C.to give the 2-substituted amino-nicotinic acid 156. The 2-substitutedamino-nicotinic acid 156 is reacted with a substituted amine in thepresence of a coupling reagent, such as BOP-Cl and base, such as TEA toform the 2-substituted amino-nicotinamide 157.

Alternatively, 2-chloro-nicotinoyl chloride 154 (where LG is Cl) iscoupled first with R²—NH₂, such as in the presence of base, e.g.,NaHCO₃, in a suitable solvent, such as IpOH or CH₂Cl₂, to form the amide158, then coupled with an amine 155 to yield the 2-substitutedamino-nicotinamide 157. Where A is a pi-electron rich heterocycle, theaddition of KF, such as 40% KF on alumina in IpOH, at a temperature overabout 100° C., preferably about 160° C., can be used in the formation of157 from 158.

2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-ylamine may be prepared bythe method found in Scheme 48. Nitrobenzylpyridines 159 are alkylated,such as with MeI, in the presence of TBAI and base to form thepyridinium compound 160. The pyridinium compounds 160 are halogenated,such as brominated with NBS, to form the brominated pyridinium compounds161 which are reduced such as with NaBH₄ to form thetetrahydro-pyridines 162. Palladium catalyzed intramolecular Heckcoupling followed by hydrogenation forms the hexahydro-fluorenes 164.

The starting compounds defined in Schemes 1-48 may also be present withfunctional groups in protected form if necessary and/or in the form ofsalts, provided a salt-forming group is present and the reaction in saltform is possible. If so desired, one compound of formulas I-XII can beconverted into another compound of formulas I-XII or a N-oxide thereof;a compound of formulas I-XII can be converted into a salt; a salt of acompound of formulas I-XII can be converted into the free compound oranother salt; and/or a mixture of isomeric compounds of formulas I-XIIcan be separated into the individual isomers.

N-Oxides can be obtained in a known matter by reacting a compound offormulas I-XII with hydrogen peroxide or a peracid, e.g.3-chloroperoxy-benzoic acid, in an inert solvent, e.g. dichloromethane,at a temperature between about −10-35° C., such as about 0° C.-RT.

If one or more other functional groups, for example carboxy, hydroxy,amino, or mercapto, are or need to be protected in a compound offormulas I-XII or in the synthesis of a compound of formulas I-XII,because they should not take part in the reaction, these are such groupsas are usually used in the synthesis of peptide compounds, and also ofcephalosporins and penicillins, as well as nucleic acid derivatives andsugars.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they lend themselves readily, i.e. withoutundesired secondary reactions, to removal, typically by solvolysis,reduction, photolysis or also by enzyme activity, for example underconditions analogous to physiological conditions, and that they are notpresent in the end-products. The specialist knows, or can easilyestablish, which protecting groups are suitable with the reactionsmentioned above and hereinafter.

The protection of such functional groups by such protecting groups, theprotecting groups themselves, and their removal reactions are describedfor example in standard reference works, such as J. F. W. McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, London and NewYork 1973, in T. W. Greene, “Protective Groups in Organic Synthesis”,Wiley, New York 1981, in “The Peptides”; Volume 3 (editors: E. Gross andJ. Meienhofer), Academic Press, London and New York 1981, in “Methodender organischen Chemie” (Methods of organic chemistry), Houben Weyl, 4thedition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jescheit, “Aminosäuren, Peptide, Proteine” (Amino acids,peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideand Derivate” (Chemistry of carbohydrates: monosaccharides andderivatives), Georg Thieme Verlag, Stuttgart 1974.

In the additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected forexample by one or more of the protecting groups mentioned above under“protecting groups”. The protecting groups are then wholly or partlyremoved according to one of the methods described there.

Salts of a compound of formulas I-XII with a salt-forming group may beprepared in a manner known per se. Acid addition salts of compounds offormulas I-XII may thus be obtained by treatment with an acid or with asuitable anion exchange reagent. A salt with two acid molecules (forexample a dihalogenide of a compound of formulas I-XII) may also beconverted into a salt with one acid molecule per compound (for example amonohalogenide); this may be done by heating to a melt, or for exampleby heating as a solid under a high vacuum at elevated temperature, forexample from about 130° C. to about 170° C., one molecule of the acidbeing expelled per molecule of a compound of formulas I-XII.

Salts can usually be converted to free compounds, e.g. by treating withsuitable basic agents, for example with alkali metal carbonates, alkalimetal hydrogen carbonates, or alkali metal hydroxides, typicallypotassium carbonate or sodium hydroxide.

A compound of formulas I-XII, wherein Z is oxygen, can be converted intothe respective compound wherein Z is sulfur, for example, by using anappropriate sulfur compound, e.g. using reaction with Lawesson's reagent(2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)in a halogenated hydrocarbon, such as CH₂Cl₂, or an aprotic solvent,such as toluene or xylene, at temperatures from about 30° C. to reflux.

All process steps described here can be carried out under known reactionconditions, preferably under those specifically mentioned, in theabsence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralizing agents, for example ion exchangers, typically cationexchangers, for example in the H+ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from about −100° C. to about 190° C.,preferably from about −80° C. to about 150° C., for example at about −80to about 60° C., at RT, at about −20 to about 40° C. or at the boilingpoint of the solvent used, under atmospheric pressure or in a closedvessel, where appropriate under pressure, and/or in an inert atmosphere,for example under argon or nitrogen.

Salts may be present in all starting compounds and transients, if thesecontain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

In certain cases, typically in hydrogenation processes, it is possibleto achieve stereoselective reactions, allowing for example easierrecovery of individual isomers.

The solvents from which those can be selected which are suitable for thereaction in question include for example water, esters, typically loweralkyl-lower alkanoates, e.g., ethyl acetate, ethers, typically aliphaticethers, e.g., diethylether, or cyclic ethers, e.g., THF, liquid aromatichydrocarbons, typically benzene or toluene, alcohols, typically MeOH,EtOH or 1-propanol, IPOH, nitriles, typically CH₃CN, halogenatedhydrocarbons, typically CH₂Cl₂, acid amides, typically DMF, bases,typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids,typically lower alkanecarboxylic acids, e.g., AcOH, carboxylic acidanhydrides, typically lower alkane acid anhydrides, e.g., aceticanhydride, cyclic, linear, or branched hydrocarbons, typicallycyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g.,aqueous solutions, unless otherwise stated in the description of theprocess. Such solvent mixtures may also be used in processing, forexample in chromatography.

The invention relates also to those forms of the process in which onestarts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described above as preferred.

The compounds of formulas I-XII, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallization (present as solvates).

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inthe preferred embodiment, such starting materials are used and reactionconditions so selected as to enable the preferred compounds to beobtained.

Starting materials of the invention, are known, are commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art.

For example, amine 1 can be prepared by reduction of the correspondingnitro. The reduction preferably takes place in the presence of asuitable reducing agent, such as tin(II) chloride or hydrogen in thepresence of an appropriate catalyst, such as Raney nickel (thenpreferably the hydrogen is used under pressure, e.g. between 2 and 20bar) or Pt0₂, in an appropriate solvent, e.g. an alcohol, such as MeOH.The reaction temperature is preferably between about 0° C. and about 80°C., especially about 15° C. to about 30° C.

It would also be possible to reduce the nitro compound after forming theamide compound under reaction conditions analogous to those for thereduction of nitro compounds described above. This would eliminate theneed to protect the free amino group as described in Scheme 1.

In the preparation of starting materials, existing functional groupswhich do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the examples.

All remaining starting materials are known, capable of being preparedaccording to known processes, or commercially obtainable; in particular,they can be prepared using processes as described in the examples.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

The compounds of this invention may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures, scalemicmixtures, single enantiomers, individual diastereomers anddiastereomeric mixtures. All such isomeric forms of these compounds areexpressly included in the present invention.

The compounds of this invention may also be represented in multipletautomeric forms, for example, as illustrated below:

The invention expressly includes all tautomeric forms of the compoundsdescribed herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

The compounds of this invention may contain heterocyclic ring systemsattached to another ring system. Such heterocyclic ring systems may beattached through a carbon atom or a heteroatom in the ring system.

Alternatively, a compound of any of the formulas delineated herein maybe synthesized according to any of the processes delineated herein. Inthe processes delineated herein, the steps may be performed in analternate order and may be preceded, or followed, by additionalprotection/deprotection steps as necessary. The processes may furthercomprise use of appropriate reaction conditions, including inertsolvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine,K₂CO₃, and the like), catalysts, and salt forms of the above. Theintermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase,simulated moving bed (“SMB”)), extraction, distillation, trituration,reverse phase HPLC and the like. Reactions conditions such astemperature, duration, pressure, and atmosphere (inert gas, ambient) areknown in the art and may be adjusted as appropriate for the reaction.

As can be appreciated by the skilled artisan, the above syntheticschemes are not intended to comprise a comprehensive list of all meansby which the compounds described and claimed in this application may besynthesized. Further methods will be evident to those of ordinary skillin the art. Additionally, the various synthetic steps described abovemay be performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theinhibitor compounds described herein are known in the art and include,for example, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons(1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); A. Katritzky and A.Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd) Ed. (2001); M.Bodanszky, A. Bodanszky: The practice of Peptide SynthesisSpringer-Verlag, Berlin Heidelberg 1984; J. Seyden-Penne: Reductions bythe Alumino-and Borohydrides in Organic Synthesis, 2^(nd) Ed.,Wiley-VCH, 1997; and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The following examples contain detailed descriptions of the methods ofpreparation of compounds of Formulas I-XII. These detailed descriptionsfall within the scope, and serve to exemplify, the above describedGeneral Synthetic Procedures which form part of the invention. Thesedetailed descriptions are presented for illustrative purposes only andare not intended as a restriction on the scope of the invention.

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. Anhydrous solvents suchas DMF, THF, CH₂Cl₂ and toluene were obtained from the Aldrich ChemicalCompany. All reactions involving air- or moisture-sensitive compoundswere performed under a nitrogen atmosphere. Flash chromatography wasperformed using Aldrich Chemical Company silica gel (200-400 mesh, 60A)or Biotage pre-packed column. Thin-layer chromatography (TLC) wasperformed with Analtech gel TLC plates (250μ). Preparative TLC wasperformed with Analtech silica gel plates (1000-2000μ). Preparative HPLCwas conducted on Beckman or Waters HPLC system with 0.1% TFA/H₂O and0.1% TFA/CH₃CN as mobile phase. The flow rate was at 20 ml/min. andgradient method was used. ¹H NMR spectra were determined with superconducting FT NMR spectrometers operating at 400 MHz or a Varian 300 MHzinstrument. Chemical shifts are expressed in ppm downfield from internalstandard tetramethylsilane. All compounds showed NMR spectra consistentwith their assigned structures. Mass spectra (MS) were determined on aPerkin Elmer-SCIEX API 165 electrospray mass spectrometer (positive and,or negative) or an HP 1100 MSD LC-MS with eletrospray ionization andquadrupole detection. All parts are by weight and temperatures are inDegrees centigrade unless otherwise indicated.

The following abbreviations are used:

-   AIBN—2,2′-azobisisobutyronitrile-   Ar—argon-   AgSO₄—silver sulfate-   ATP—adenosine triphosphate-   BH₃—borane-   Boc—tert-butyloxycarbonyl-   Boc₂O—Boc anhydride-   BOP-Cl—bis(2-oxo-3-oxazolidinyl)phosphinic chloride-   Br₂—bromine-   BSA—bovine serum albumin-   t-BuOH—tert-butanol-   CAN—ammonium cerium(IV) nitrate-   CH₃CN, AcCN—acetonitrile-   CH₂Cl₂—dichloromethane-   CH₃I, MeI—iodomethane, methyl iodide-   CCl₄—carbon tetrachloride-   CCl₃—chloroform-   CO₂—carbon dioxide-   Cs₂CO₃—cesium carbonate-   DIEA—diisopropylethylamine-   CuI—copper iodide-   DCE—1,2-dichloroethane-   DEAD—diethyl azodicarboxylate-   DIEA—diisopropylethylamine-   dppf—1,1-diphenylphosphinoferrocene-   DMAP—4-(dimethylamino)pyridine-   DMAC—N,N-dimethylacetamide-   DMF—dimethylformamide-   DMSO—dimethylsulfoxide-   DTT—dithiothreitol-   EDC, EDAC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    hydrochloride-   EGTA—ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic    acid-   EtOAc—ethyl acetate-   EtOH—ethanol-   Et₂O—diethyl ether-   Fe—iron-   g—gram-   h—hour-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   H₂—hydrogen-   H₂O—water-   HCl—hydrochloric acid-   H₂SO₄—sulfuric acid-   H₂NNH₂—hydrazine-   HC(OEt)₃—triethylorthoformate-   HCHO, H₂CO—formaldehyde-   HCO₂Na—sodium formate-   HOAc, AcOH—acetic acid-   HOAt—1-hydroxy-7-azabenzotriazole-   HOBt—hydroxybenzotriazole-   IpOH—isopropanol-   K₂CO₃—potassium carbonate-   KHMDS—potassium hexamethylsilazane-   KNO₃—potassium nitrate-   KOAc—potassium acetate-   KOH—potassium hydroxide-   LAH, LiAlH₄—lithium aluminum hydride-   LDA—lithium diisopropylamide-   LiCl—lithium chloride-   LiHMDS—lithium hexamethyldisilazide-   MeOH—methanol-   MgCl₂—magnesium chloride-   MgSO₄—magnesium sulfate-   mg—milligram-   ml—milliliter-   MnCl₂—manganese chloride-   NBS—N-bromosuccinimide-   NMO—4-methylmorpholine, N-oxide-   NMP—N-methylpyrrolidone-   Na₂SO₄—sodium sulfate-   Na₂S₂O₅—sodium metabisulfite-   NaHCO₃—sodium bicarbonate-   Na₂CO₃—sodium carbonate-   NaCl—sodium chloride-   NaH—sodium hydride-   NaI—sodium iodide-   NaOH—sodium hydroxide-   NaOMe—sodium methoxide-   NaCNBH₃—sodium cyanoborohydride-   NaBH₄—sodium borohydride-   NaNO₂—sodium nitrate-   NaBH(OAc)₃—sodium triacetoxyborohydride-   NH₄Cl—ammonium chloride-   N₂—nitrogen-   Pd/C—palladium on carbon-   PdCl₂(PPh₃)₂—palladium chloride bis(triphenylphosphine)-   PdCl₂(dppf)—1,1-bis(diphenylphosphino)ferrocene palladium chloride-   Pd(PPh₃)₄—palladium tetrakis triphenylphosphine-   Pd(OH)₂—palladium hydroxide-   Pd(OAc)₂—palladium acetate-   PMB—para methoxybenzyl-   POCl₃—phosphorus oxychloride-   PPh₃—triphenylphosphine-   PtO₂—platinum oxide-   RT—room temperature-   SiO₂—silica-   SOCl₂—thionyl chloride-   TBAI—tetrabutylammonium iodide-   TEA—triethylamine-   Tf₂NPh—N-phenyltrifluoromethanesulfonimide-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran-   TPAP—tetrapropylammoniumperruthenate-   Tris-HCl—Tris(hydroxymethyl)aminomethane hydrochloride salt-   Zn—zinc

Preparation I—3-nitro-5-trifluoromethyl-phenol

1-Methoxy-3-nitro-5-trifluoromethyl-benzene (10 g, Aldrich) andpyridine-HCl (41.8 g, Aldrich) were mixed together and heated neat at210° C. in an open flask. After 2.5 h the mixture was cooled to RT andpartitioned between 1N HCl and EtOAc. The EtOAc fraction was washed with1N HCl (4×), brine (1×), dried with Na₂SO₄, filtered and concentrated invacuo to form 3-nitro-5-trifluoromethyl-phenol as an off-white solid.

Preparation II—1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine

3-Nitro-5-trifluoromethyl-phenol (8.81 g) was dissolved in THF (76 ml).1-Boc-4-hydroxy-piperidine (8.81 g, Aldrich) and Ph₃P (11.15 g) wereadded and the solution was cooled to −20° C. A solution of DEAD (6.8 ml,Aldrich) in THF (36 ml) was added dropwise, maintaining the temperaturebetween −20 and −10° C. The reaction was warmed to RT and stirredovernight. The reaction was concentrated in vacuo and triturated withhexane. The yellow solid was removed by filtration and washed with Et₂O(25 ml), and hexane. The white filtrate was washed with 1N NaOH (2×),brine (1×) and the hexane layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was purified with flashchromatography (SiO₂, 5-10% EtOAc/hexane) to obtain1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) (S)-1-Boc-[2-(5-nitro-2-trifluoromethylphenoxymethyl]-pyrrolidine-   b)    (R)-1-Boc-[2-(5-nitro-2-trifluoromethylphenoxymethyl]-pyrrolidine.-   c) (R)1-Boc-2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine-   d) 4-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-methyl-piperidine.-   e) (S)1-Boc-2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine-   f) 1-Boc-3-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-azetidine.-   g) N-Boc-[2-(5-nitro-2-pentafluoroethyl-phenoxy)-ethyl]amine.-   h) (R)3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-pyrrolidine.-   i) 3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-azetidine.-   j) (S)-1-Boc-[2-(5-nitro-2-tert-butylphenoxymethyl]-pyrrolidine-   k) (S)3-(2-tert-Butyl-5-nitro-phenoxymethyl)-1-Boc-pyrrolidine.-   l) (R)-1-Boc-[2-(5-nitro-2-tert-butylphenoxymethyl]-pyrrolidine

Preparation III—1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine

1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine (470 mg) wasdissolved in MeOH (12 ml) and Pd/C (10 mg) was added. After spargingbriefly with H₂, the mixture was stirred under H₂ for 6 H. The catalystwas removed by filtration and the MeOH solution was concentrated invacuo to yield 1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine asan off-white foam.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 1-Boc-2-(3-Amino-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.-   b) 2-(3-Amino-5-trifluoromethyl-phenoxymethyl)-1-methyl-pyrrolidine.-   c) [2-(1-Methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine. ESI    (M+H)=222.-   d) [2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-yl]methylamine.-   e) [2-(2-Morpholin-4-yl-propoxy)-pyridin-4-yl]methylamine.-   f) [2-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-yl]methylamine.    ESI MS: (M+H)=222.-   g) (4-Aminomethyl-pyridin-2-yl)-(3-morpholin-4-yl-propyl)-amine. ESI    MS: (M+H)=251.-   h) 4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine.-   i) 4-tert-Butyl-3-(2-piperidin-1-yl-ethoxy)-phenylamine.-   j)    3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenylamine.-   k)    3-(1-Isopropyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenylamine.-   l) (S)3-Oxiranylmethoxy-4-pentafluoroethyl-phenylamine.-   m) 3-(2-Pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine.-   n) 3-(2-Piperidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine.-   o)    (S)3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine.-   p)    (R)3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine.-   q)    (R)3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.-   r)    (S)3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine-   s) (R)3-Oxiranylmethoxy-4-pentafluoroethyl-phenylamine.-   t)    (R)2-(5-Amino-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-yl-ethanol.-   u) 3-(1-Boc-azetidin-3-ylmethoxy)-4-pentafluoroethyl-phenylamine.-   v) 3-(2-(Boc-amino)ethoxy)-4-pentafluoroethyl-phenylamine.-   w) 6-Amino-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one. M+H 193.2. Calc'd    192.1.-   x) 2,2,4-Trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamine.-   y)    1-(6-Amino-2,2-dimethyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethanone.    M+H 221.4. Calc'd 220.3.-   z) [2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-yl]-methylamine.-   aa) [2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-yl]-methylamine.    M+H 236.3. Calc'd 235.2.-   ab) 3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine.    M+H 360.3.-   ac) 2-Boc-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-ylamine.-   ad) 3-Morpholin-4-ylmethyl-4-pentafluoroethyl-phenylamine.-   ae)    3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenylamine.    M+H 410.3. Calc'd 409.4.-   af)    7-Amino-2-(4-methoxy-benzyl)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one.    M+H 311.1.-   ag) 7-Amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one.-   ah)    (3-Amino-5-trifluoromethyl-phenyl)-(4-Boc-piperazin-1-yl)-methanone.    M+H 374.3; Calc'd 373.-   ai) 3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine.-   aj)    1-(7-Amino-4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone.    M+H 219.2.-   ak) {2-[2-(1-Methylpiperidin-4-yl)ethoxy]-pyridin-4-yl}-methylamine.-   al) {2-[2-(1-Pyrrolidinyl)ethoxy]-pyridin-4-yl}-methylamine.-   am) {2-[2-(1-Methylpyrrolin-2-yl)ethoxy]-pyridin-4-yl}-methylamine.-   an) (2-Chloro-pyrimidin-4-yl)-methylamine.-   ao) 3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenylamine.-   ap) 4-tert-Butyl-3-(1-Boc-pyrrolidin-3-ylmethoxy)-phenylamine. M+H    385.-   aq) 4-tert-Butyl-3-(1-Boc-azetidin-3-ylmethoxy)-phenylamine. M+Na    357.-   ar) (S)4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenylamine.    M+Na 371.-   as) 3-tert-Butyl-4-(4-Boc-piperazin-1-yl)-phenylamine-   at) 3-(1-Methyl-piperidin-4-yl)-5-trifluoromethyl-phenylamine.-   au) 3,3-Dimethyl-2,3-dihydro-benzofuran-6-ylamine.-   av)    3,9,9-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-ylamine.-   aw) 4-[1-Methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenylamine was    prepared using EtOH as the solvent.-   ax) 4-tert-Butyl-3-(4-pyrrolidin-1-yl-but-1-enyl)-phenylamine.-   ay)    (R)3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.-   az)    (S)3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenylamine.

PreparationIV—1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine

1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine (4.37 g) wasdissolved in CH₂Cl₂ (100 ml) and NaHCO₃ (2.4 g, Baker) was added.2-Fluoropyridine-3-carbonyl chloride (2.12 g) was added an the reactionwas stirred at RT for 2.5 h. The reaction was filtered and concentratedin vacuo to yield a yellow foam. (30%) EtOAc/Hexane was added and1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidineprecipitated as an off white solid.

The following compounds were prepared similarly to the procedureoutlined above:

-   a)    2-Fluoro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.-   b)    N-[4-tert-Butyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-fluoro-nicotinamide.-   c)    N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.-   d)    N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide-   e)    N-[3,3-Dimethyl-1-(2-(Boc-amino)acetyl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.-   f)    N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-fluoro-nicotinamide.    M+H 344.5. Calc'd 343.4.-   g)    2-Fluoro-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide.    M+H 316.2. Calc'd 315.1.-   h)    N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-fluoro-nicotinamide.    M+H 316.1. Calc'd 315.10.-   i)    2-Fluoro-N-[3-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.    M+H 481. Calc'd 480.-   j)    2-Fluoro-N-(2-Boc-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.    M+H 400.-   k)    2-Fluoro-N-[3-(4-methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-nicotinamide.    M+H 447.0. Calc'd 446.-   l)    2-Fluoro-N-(3-morpholin-4-ylmethyl-4-pentafluoroethyl-phenyl)-nicotinamide.-   m) 2-Fluoro-N-[4-iodophenyl]-nicotinamide.-   n)    2-Fluoro-N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.    M+H 314.0, Calc'd 311.-   o)    2-Fluoro-N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-nicotinamide.    M+H 495.-   p)    2-Fluoro-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.    M+H 483.3; Calc'd 482.-   q)    N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-fluoro-nicotinamide.    M+H 430.0.-   r)    N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.    M+H 383.2; Calc'd 382.5.-   s) N-(4-tert-Butylphenyl)-2-fluoronicotinamide.-   t) N-(4-Trifluoromethylphenyl)-2-fluoronicotinamide.-   u)    2-Fluoro-N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.    M−H 468.2; Calc'd 469.16.-   v)    2-Fluoro-N-[3-(1-Boc-azetidin-3-ylmethoxy)-4-tert-butyl-phenyl]-nicotinamide.-   w)    (S)N-[4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-fluoro-nicotinamide.    M+Na 494.-   x)    N-[3-(1-Methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-2-fluoro-nicotinamide    was prepared with K₂CO₃. instead of NaHCO₃.-   y) N-(3-Bromo-5-trifluoromethyl-phenyl)-2-fluoro-nicotinamide.-   z)    2-Fluoro-N-(3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-nicotinamide.-   aa)    2-Fluoro-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide-   ab)    N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide.

PreparationV—1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine

1-Boc-4-[3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy]-piperidinewas prepared from 1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidineand 2-chloropyridine-3-carbonyl chloride by a procedure similar to thatdescribed in the preparation of1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) N-(4-tert-Butyl-3-nitro-phenyl)-2-chloro-nicotinamide.-   b)    2-Chloro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.-   c)    2-Chloro-N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.-   d)    2-Chloro-N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide.-   e)    2-Chloro-N-[3-(1-methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.-   f)    2-Chloro-N-[3-(1-isopropyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.-   g)    (S)2-Chloro-N-[4-(oxiranylmethoxy)-3-pentafluoroethyl-phenyl]-nicotinamide.-   h)    2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide.-   i)    2-Chloro-N-[3-(2-piperidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.-   j)    (R)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.-   k)    (S)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide.-   l)    (R)2-Chloro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.-   m)    (S)2-Chloro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.-   n)    (R)2-Chloro-N-[4-(oxiranylmethoxy)-3-pentafluoroethyl-phenyl]-nicotinamide.-   o) (R)Acetic acid    2-{5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy}-1-pyrrolidin-1-yl-ethyl    ester.-   p)    2-Chloro-N-[3-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.-   q)    2-Chloro-N-[2-(4-methoxy-benzyl)-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-nicotinamide.    M+H 450.2. Calc'd 449.-   r)    2-Chloro-N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide.    M+H 330.1, Calc'd 329.-   s)    2-Chloro-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.-   t)    2-{3-[(2-Chloro-pyridine-3-carbonyl)-amino]-phenyl}-2-methyl-propionic    acid methyl ester. M+H 405-   u)    N-[4-tert-Butyl-3-[2-(1-Boc-piperidin-4-yl)-ethyl]-phenyl]-2-chloro-nicotinamide.    M+Na 524. Calc'd 501.1.-   v)    N-[3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-benzo[d]isothiazol-6-yl]-2-chloro-nicotinamide.-   w)    N-[1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-yl]-2-chloro-nicotinamide.-   x)    2-Chloro-N-[3,3-dimethyl-2,3-dihydro-benzofuran-6-yl]-2-chloro-nicotinamide.-   y)    2-Chloro-N-[3-(1-Boc-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide.-   z)    2-Chloro-N-[3-(1-methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.-   aa)    2-Chloro-N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-nicotinamide.-   ab)    N-[4-tert-Butyl-3-(4-pyrrolidin-1-yl-but-1-enyl)-phenyl]-2-chloro-nicotinamide.-   ac)    (R)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.-   ad)    (S)2-Chloro-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.

PreparationVI—1-Boc-2-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidine

1-Boc-2-{3-[(2-Fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidinewas prepared from1-Boc-2-(3-amino-5-trifluoromethyl-phenoxymethyl)-pyrrolidine by aprocedure similar to that described in the preparation of1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation VII—2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

1-Boc-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (2.35 g)was dissolved in CH₂Cl₂ (60 ml) and TFA (20 ml) was added. Afterstirring for 1 h at RT, the mixture was concentrated in vacuo to yield2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine as an oil thatsolidified upon standing. The material was used as is without furtherpurification.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) (4-Aminomethyl-pyrimidin-2-yl)-(3-morpholin-4-yl-propyl)-amine.-   b)    (4-Aminomethyl-pyrimidin-2-yl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine.

PreparationVIII—1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine

2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) wasdissolved in CH₃CN (20 ml) and formaldehyde (2.4 ml, 37% aqueous) wasadded. NaBH₃CN (607 mg) was added, an exotherm was observed. The pH ismonitored every 15 min and adjusted to ˜7 with AcOH. After 45 min, themixture was concentrated in vacuo and the residue is dissolved in EtOAc,washed with 6N NaOH, 1N NaOH, and 2N HCl (3×). The acid washings werecombined, adjusted to ˜pH 10 with solid Na₂CO₃ and extracted with EtOAc(2×). The EtOAc fractions were combined, dried with Na₂SO₄, and purifiedwith flash chromatography (SiO₂, 95:5:0.5 CH₂Cl₂:MeOH:NH₄OH) to afford1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 2-(1-Methylpiperidin-4-yl)-ethanol.-   b)    2-{3-[(2-Fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-1-methylpyrrolidine.

Preparation IX—4-tert-butyl-3-nitro-phenylamine

A mixture of 1,3-dinitro-4-tert-butylbenzene (10.0 g) in H₂O (56 ml) washeated to reflux. A mixture of Na₂S (21.42 g) and sulfur (2.85 g) in H₂O(34 ml) was added over 1 h via an addition funnel. The reactionmaintained at reflux for 1.5 h then cooled to RT and extracted withEtOAc. The organic extracts were combined and washed with H₂O, brine,dried over MgSO₄ and concentrated in vacuo to afford4-tert-butyl-3-nitro-phenylamine which was used as is without furtherpurification.

Preparation X—N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide

3-Bromo-5-(trifluoromethyl)phenylamine (5 g, Alfa-Aesar) was dissolvedin AcOH (140 ml) and Ac₂O (5.9 ml, Aldrich) was added. The reaction wasstirred at RT overnight. The mixture was added slowly to H₂O (˜700 ml)forming a white precipitate. The solid was isolated by filtration,washed with H₂O and dried under vacuum to yieldN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide.

PreparationXI—N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide

Allylpiperidine (1.96 g, Lancaster) was degassed under vacuum, dissolvedin 0.5 M 9-BBN in THF (31.2 ml, Aldrich), and heated to reflux for 1 h,then cooled to RT. PD (dppf)Cl₂/CH₂Cl₂ was added to a degassed mixtureof N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide, K₂CO₃ (9.8 g) DMF(32.1 ml and H₂O (3 ml). The allyl piperidine solution was added heatedto 60° C. for 3 h. After cooling to RT and reheating at 60° C. for 6 h,the mixture was cooled to RT and poured into H₂O. The mixture wasextracted with EtOAc (2×), and the EtOAc portion was washed with 2 N HCl(2×) and brine. The aqueous phases were combined and the pH was adjustedto ˜11 with NaOH (15%) forming a cloudy suspension. The cloudysuspension was extracted with EtOAc (2×) and the EtOAc portion was driedwith Na₂SO₄, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (SiO₂, 95:5:0.5 CH₂Cl₂:MeOH:NH₄OH) toaffordN-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide as abrown oil that solidified under vacuum.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) N-(3-Morpholin-4-ylpropyl-5-trifluoromethyl-phenyl)-acetamide    from 4-allyl-morpholine.-   b)    N-(3-(1-methylpiperidin-4-ylmethyl-5-trifluoromethyl-phenyl)-acetamide    from 1-Methyl-4-methylene-piperidine.

PreparationXII—3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine

N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide (1.33g) was dissolved in EtOH (40 ml) and 12 N HCl (40 ml) was added. Afterstirring overnight at 70° C. and RT, the mixture was concentrated invacuo, affording3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine as a brownoil.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 3,3-Dimethyl-6-nitro-2,3-dihydro-1H-indole. M+H 193.1; Calc'd    192.2.-   b) 3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenylamine.-   c) 3-Morpholin-4-ylmethyl-5-trifluoromethyl-phenylamine.

PreparationXIII—3,3-Dimethyl-6-nitro-1-piperidin-4-ylmethyl-2,3-dihydro-1H-indole

3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indolewas dissolved in HCl/EtOAc and stirred for 2 h. The mixture wasconcentrated in vacuo and partitioned between 1,2-dichloroethane and 1NNaOH. The organic layer was removed, washed with brine, dried (Na₂SO₄)and filtered. The material was used without further purification.

PreparationXIV—N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide

N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide wasprepared from allyl morpholine andN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide similar to that describedin the preparation ofN-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.

Preparation XV—3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenylamine

3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenylamine was preparedfrom N-[3-(3-morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamidesimilar to that described in the preparation of3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine.

Preparation XVI—1-methyl-4-methylene-piperidine

Ph₃PCH₃I (50 g, Aldrich) was suspended in Et₂O (20 ml) and butyllithium(77.3 ml, 1.6 M in hexanes, Aldrich) was added dropwise. The reactionwas stirred for 2 h at RT then 1-methylpiperidone (12.3 ml, Aldrich) wasadded slowly. The mixture was stirred at RT overnight. The solid wasremoved by filtration, the volume was reduced to ˜400 ml and additionalsolid was removed by filtration. The Et₂O was washed with H₂O (2×) and2N HCl (4×). The pH of the acid washings was adjusted to −11 with 6 NNaOH, then they were extracted with CH₂Cl₂ (4×). The CH₂Cl₂ washingswere dried over Na₂SO₄ and concentrated cold in vacuo to provide1-methyl-4-methylene-piperidine which was used as is.

PreparationXVII—N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamide

N-[3-(1-Methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamide wasprepared from 1-methyl-4-methylene-piperidine andN-(3-bromo-5-trifluoromethyl-phenyl)-acetamide similar to that describedin the preparation ofN-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.

PreparationXVIII—3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenylamine

3-(1-Methylpiperidin-4-yl)-5-trifluoromethyl-phenylamine was preparedfrom N-[3-(1-methylpiperidin-4-yl)-5-trifluoromethyl-phenyl]-acetamidesimilar to the procedure described in the preparation of3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine.

Preparation XIX—2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile

4-Hydroxy-1-methylpiperidine (25.4 g) was dissolved in THF (50 ml) in a100 mL r.b. flask. NaH/mineral oil mixture (9.58 g) was slowly added tothe flask and stirred for 20 min. 2-Chloro-4-cyanopyridine was added tothe mixture and stirred at RT until completion. Diluted mixture withEtOAc and added H₂O to quench mixture, then transferred contents to asep. funnel. The organic phase was collected while the aqueous phase waswashed two times with EtOAc. The combined organics were dried overNa₂SO₄, filtered, then concentrated in vacuo. Then redissolved mixturein CH₂Cl₂, 10% HCl (300 ml) was added and the mixture was transferred tosep. funnel. The org. was extracted, while EtOAc along with 300 mL 5NNaOH was added to the sep. funnel. The organic phases were collected,dried over Na₂SO₄, filtered and concentrated in vacuo affording2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile as a brown solid.ESI (M+H)=218.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 2-(1-methylpiperidin-4-ylmethoxy)-4-pyridylcarbonitrile. M+H    232.1. Calc'd 231.1.-   b) 2-(1-Benzhydryl-azetidin-3-yloxy)-4-pyridylcarbonitrile. M+H    342.2. Calc'd 341.2.-   c) 2-(1-methylpiperidin-4-ylethoxy)-4-pyridylcarbonitrile.-   d) 2-(1-pyrrolidinylethoxy)-4-pyridylcarbonitrile.-   e) 2-(1-methylpyrrolin-2-ylethoxy)-4-pyridylcarbonitrile.-   f) 2-[2-(1-Boc-azetidin-3-yl)-ethoxy]-4-pyridylcarbonitrile.

Preparation XX—[2-(1-methylpiperidin-4-yloxy)-pyridin-4-yl]methylaminebis hydrochloride

[2-(1-Methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine was diluted withEt₂O (50 ml) and 1M HCl/Et₂O (47 ml) was added. The vessel was swirleduntil precipitate formed.

Preparation XXI—2-(2-morpholin-4-yl-ethoxy)-4-pyridylcarbonitrile

2-(2-Morpholin-4-yl-ethoxy)-4-pyridylcarbonitrile was prepared from2-chloro-4-cyanopyridine and 2-morpholin-4-yl-ethanol by a proceduresimilar to that described in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile. The hydrochloridesalt was prepared similar to that described for[2-(1-methylpiperidin-4-yloxy)-pyridin-4-yl]methylamine bishydrochloride.

Preparation XXII—2-morpholin-4-yl-propanol

LAH powder (1.6 g) was added to a flask while under N₂ atmosphere,immediately followed by THF (50 ml). The mixture was chilled to 0° C.,methyl 2-morpholin-4-yl-propionate (5 g) was added dropwise to thereaction mixture and stirred at 0° C. After 1 h, the mixture was workedup by adding H₂O (44 mL), 2N NaOH (44 mL), then H₂O (44 mL, 3×). After30 min of stirring, the mixture was filtered through Celite® and theorganic portion was concentrated in vacuo providing2-morpholin-4-yl-propanol as a colorless oil.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) (1-Methyl-piperidin-4-yl)-methanol. M+H 130.2. Calc'd 129.1.

Preparation XXIII—2-(2-morpholin-4-yl-propoxy)-4-pyridylcarbonitrile

2-(2-Morpholin-4-yl-propoxy)-4-pyridylcarbonitrile was prepared from2-chloro-4-cyanopyridine and 2-morpholin-4-yl-propanol by a proceduresimilar to that described in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile.

PreparationXXIV—2-(1-Methyl-pyrrolidin-2-ylmethoxy)-4-pyridylcarbonitrile

2-(1-Methyl-pyrrolidin-2-ylmethoxy)-4-pyridylcarbonitrile was preparedfrom 2-chloro-4-cyanopyridine and 1-methyl-pyrrolidin-2-ylmethanol by aprocedure similar to that described in the preparation of2-(1-methylpiperidin-4-yloxy)-4-pyridylcarbonitrile. ESI MS: (M+H)=218.

Preparation XXV—2-(3-morpholin-4-yl-propylamino)-4-pyridylcarbonitrile

To a flask charged with 2-chloro-4-cyanopyridine (2.0 g), was added theaminopropyl morpholine (2.11 ml). The mixture was heated to 79° C. for 5h and stirred. After 5 h the reaction was incomplete. The mixture wasthen heated at 60° C. overnight. The crude compound was purified onsilica gel (1-5% MeOH/CH₂Cl₂ gradient). ESI MS: (M+H)=247, (M−H)=245.

Preparation XXVI—5-Nitro-2-pentafluoroethylphenol

Combined 2-methoxy-4-nitro-1-pentafluoroethylbenzene (9.35 g) andpyridine hydrochloride in a round bottom flask and heated at 210° C. for1 h then cooled to RT. The mixture was diluted with EtOAc and 2N HCl(>500 ml) until all residue dissolved. The organic layer was removed,washed with 2N HCl (2×) and concentrated in vacuo. The residue wasdissolved in hexanes and Et₂O, washed with 2N HCl, then brine. Driedorganic layer over Na₂SO₄, filtered, concentrated in vacuo and driedunder high vacuum to provide 5-nitro-2-pentafluoromethylphenol.

Preparation XXVII—2-tert-Butyl-5-nitro-aniline

To H₂SO₄ (98%, 389 mL) in a 500 mL 3-neck flask was added 2-tert-butylaniline (40.6 mL). The reaction was cooled to −10° C. and KNO₃ in 3.89 galiquots was added every 6 min for a total of 10 aliquots. Tried tomaintain temperature at −5° C. to −10° C. After final addition of KNO₃,stirred the reaction for five min then it was poured onto ice (50 g).The black mix was diluted with H₂O and extracted with EtOAc. The aqueouslayer was basified with solid NaOH slowly then extracted with EtOAc(2×). The combined organic layers were washed with 6N NaOH and then witha mix of 6N NaOH and brine, dried over Na₂SO₄, filtered and concentratedin vacuo to obtain crude 2-tert-butyl-5-nitro-aniline as a darkred-black oil which solidified when standing at RT. The crude materialwas triturated with about 130 mL hexanes. After decanting the hexanes,the material was dried to obtain a dark-red black solid.

Preparation XXVIII—2-tert-Butyl-5-nitrophenol

In a 250 ml round bottom flask, 20 mL concentrated H₂SO4 was added to2-tert-butyl-5-nitro-aniline (7.15 g) by adding 5 mL aliquots of acidand sonicating with occasional heating until all of the starting anilinewent into solution. H₂O (84 ml) was added with stirring, then thereaction was cooled to 0° C. forming a yellow-orange suspension. Asolution of NaNO₂ (2.792 g) in H₂O (11.2 mL) was added dropwise to thesuspension and stirred for 5 min. Excess NaNO₂ was neutralized withurea, then the cloudy solution was transferred to 500 ml 3-necked roundbottom flask then added 17 mL of 1:2 H₂SO₄:H₂O solution, and heated atreflux. Two additional 5 mL aliquots of 1:2 H₂SO₄:H₂O solution, a 7 mLaliquot of 1:2 H₂SO₄:H₂O solution and another 10 mL of 1:2 H₂SO₄: H₂Owere added while heating at reflux. The mixture was cooled to RT forminga black layer floating on top of the aqueous layer. The black layer wasdiluted with EtOAc (300 mL) and separated. The organic layer was washedwith H₂O then brine, dried over Na₂SO₄ and concentrated in vacuo. Crudeoil was purified on silica gel column with 8% EtOAc/Hexanes. Upon dryingunder vacuum, the 2-tert-butyl-5-nitrophenol was isolated as a brownsolid.

Preparation XXIX—1-methylpiperidine-4-carboxylic acid ethyl ester

Piperidine-4-carboxylic acid ethyl ester (78 g) was dissolved in MeOH(1.2 L) at RT then formaldehyde (37%, 90 ml) and acetic acid (42 ml)were added and stirred for 2 h. The mixture was cooled to 0° C., NaCNBH₃(70 g) was added, and the mix was stirred for 20 min at 0° C., thenovernight at RT. The mixture was cooled to 0° C. then quenched with 6NNaOH. The mixture was concentrated in vacuo to an aqueous layer, whichwas extracted with EtOAc (4×), brine-washed, dried over Na₂SO₄, andconcentrated in vacuo to provide 1-methylpiperidine-4-carboxylic acidethyl ester.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) (1-Methyl-piperidin-4-yl)-methanol. M+H 130.2. Calc'd 129.1.

PreparationXXX—N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamide

N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-chloro-nicotinamidewas prepared from4-tert-butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenylamine by aprocedure similar to that described in the preparation of1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation XXXI—1-[2-(2-tert-Butyl-5-nitro-phenoxy)-ethyl]-piperidine

To 2-tert-butyl-5-nitrophenol (1.01 g) and K₂CO₃ (1.72 g) was addedacetone (35 ml) and H₂O (10.5 mL), then 1-(2-chloroethyl)piperidine HCl(1.909 g) and TBAI (153 mg). The mixture was stirred at refluxovernight. Additional K₂CO₃ (850 mg) and 1-(2-chloroethyl)-piperidineHCl (950 mg) were added and the mixture was heated at reflux for 6 h.The mixture was concentrated in vacuo to an aqueous layer which wasacidified with 2N HCl and extracted with EtOAc. The aqueous layer wasbasified with 6N NaOH and washed with CH₂Cl₂ (3×). The combined organiclayers were washed with brine/1N NaOH and dried over Na₂SO₄. Washed theEtOAc layer with 2N NaOH/brine and dried over Na₂SO₄. The crude materialwas purified by silica gel column chromatography with 15% EtOAc/Hexanesto yield 1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine as alight tan solid. (M+1)=307.3.

Preparation XXXII—1-Boc-Piperidine-4-carboxylic acid ethyl ester

To a stirred solution of piperidine-4-carboxylic acid ethyl ester (23.5g) in EtOAc (118 ml) at 0° C. was added dropwise Boc₂O in EtOAc (60 ml).The reaction was warmed to RT and stirred overnight. Washed reactionwith H₂O, 0.1N HCl, H₂O, NaHCO₃ and brine. The organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo. The liquid was driedunder vacuum to provide 1-Boc-piperidine-4-carboxylic acid ethyl ester.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) N-Boc-(2-chloropyrimidin-4-yl)-methylamine.-   b) 1-(2-tert-Butyl-4-nitrophenyl)-4-Boc-piperazine.-   c) 1-Boc-azetidine-3-carboxylic acid-   d) 1-Boc-4-Hydroxymethyl-piperidine using TEA.

Preparation XXXIII—1-Boc-4-hydroxymethyl-piperidine

1-Boc-4-Hydroxymethyl-piperidine was prepared from1-Boc-piperidine-4-carboxylic acid ethyl ester by a procedure similar tothat described in the preparation of 2-morpholin-4-yl-propanol.

Preparation XXXIV—1-Boc-4-Methylsulfonyloxymethyl-piperidine

Dissolved 1-Boc-4-hydroxymethyl-piperidine in anhydrous CH₂Cl₂ (50 ml)and TEA (4.5 ml) and cooled to 0° C. Mesyl chloride (840 μl) was addedand the mixture was stirred for 15 min then at RT for 45 min. Themixture was washed with brine/1N HCl and then brine, dried over Na₂SO₄,concentrated in vacuo and dried under high vacuum to provide1-Boc-4-methylsulfonyloxymethyl-piperidine as a yellow orange thick oil.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 1-Boc-3-methylsulfonyloxymethyl-azetidine.

PreparationXXXV—1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

To a slurry of 60% NaH suspension in DMF (30 mL) at RT added a solutionof 5-nitro-2-pentafluoroethyl-phenol (3.6 g) in 5 mL DMF. The dark redmixture was stirred at RT for 10 min then added a solution of1-Boc-4-methylsulfonyloxymethyl-piperidine (3.1 g) in 5 mL DMF. Thereaction was stirred at 60° C. and 95° C. After 1 h, added 2.94 g K₂CO₃and stirred overnight at 105° C. After cooling to RT, the reaction wasdiluted with hexanes and 1N NaOH. Separated layers, and washed organiclayer with 1N NaOH and with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification with silica gel columnchromatography with 8% EtOAc/Hexanes yielded1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine as a lightyellow thick oil.

PreparationXXXVI—4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

4-(3-Nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine was preparedfrom 1-Boc-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine by aprocedure similar to that described in the preparation of2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.

PreparationXXXVII—1-methyl-4-(3-nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine

4-(3-Nitro-6-pentafluoroethyl-phenoxymethyl)-piperidine (316.5 mg) wasdissolved in 2.7 mL acetonitrile, then added 37% formaldehyde/H₂O (360ul) and then NaBH₃CN (90 mg). Upon addition of NaCNBH₃ the reactionexothermed slightly. The reaction was stirred at RT and pH wasmaintained at ˜7 by addition of drops of glacial acetic acid. Afterabout 1 h, the mixture was concentrated in vacuo, treated with 8 mL 2NKOH and extracted two times with 10 mL Et₂O. The organic layers werewashed with 0.5N KOH and then the combined organic layers were extractedtwo times with 1N HCl. The aqueous layer was basified with solid KOH andextracted two times with Et₂O. This organic layer was then washed withbrine/1N NaOH, dried over Na₂SO₄, filtered, concentrated in vacuo anddried under high vacuum to give pure compound.

PreparationXXXVIII—1-Isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine

Dissolved 4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine (646mg) in 1,2-dichloroethane (6.4 ml), then added acetone (136 ul),NaBH(OAc)₃ (541 mg) and finally acetic acid (105 ul). Stirred the cloudyyellow solution under N₂ at RT overnight. Added another 130 uL acetoneand stirred at RT over weekend. Quenched the reaction with 30 mL NNaOH/H₂O and stirred 10 min. Extracted with Et₂O and the organic layerwas brine-washed, dried over Na₂SO₄, filtered and concentrated in vacuo.Dried under high vacuum for several h to obtain1-isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine as ayellow orange solid.

The following compounds were prepared similarly to the procedureoutlined above:

-   a)    3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indole    was prepared using 1-methyl-piperidin-4-one. M+H 290; Calc'd 289.4.-   b)    3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indole    using 1-Boc-4-formyl-piperidine.

PreparationXXXIX—3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-6-nitro-2,3-dihydro-1H-indole

3,3-Dimethyl-1-piperidin-4-ylmethyl-6-nitro-2,3-dihydro-1H-indole wastreated with an excess of formaldehyde and NaBH(OAc)₃ and stirredovernight at RT. The reaction was quenched with MeOH and concentrated invacuo. The residue was partitioned between EtOAc and 1N NaOH. Theorganic layer was removed, washed with brine, dried (Na₂SO₄), filteredand concentrated to provide the compound.

Preparation XL—(S)2-(5-Nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane

Combined 5-nitro-2-pentafluoromethylphenol (2.69 g), DMF (25 ml) K₂CO₃(3.03 g) and (S) toluene-4-sulfonic acid oxiranyl-methyl ester (2.27 g)and stirred the mixture at 90° C. After about 4 hours, the mix wascooled, diluted with EtOAc, washed with H₂O, 1N NaOH (2×), 1N HCl andthen with brine. Dried over Na₂SO₄, filtered and concentrated in vacuo.Purified the crude on silica gel column with 5% EtOAc/hexane and dryingunder high vacuum provided the(S)-2-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) (R)-2-(5-Nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane.

PreparationXLI—(S)2-Chloro-N-[3-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

(S)2-Chloro-N-[4-(2-oxiranylmethoxy-)-3-pentafluoroethyl-phenyl]-nicotinamide(1.11 g) in a sealed tube and added pyrrolidine (285 μl). Stirred aftersealing tube at 60° C. After 12 h, the mix was concentrated in vacuo andpurified on a silica gel column (5:95:0.5 MeOH:CH₂Cl₂:NH₄OH-8:92:1,MeOH:CH₂Cl₂:NH₄OH). Concentrated in vacuo and dried under high vacuum toobtain pure compound.

The following compounds were prepared similarly to the procedureoutlined above:

-   a)    (R)1-(5-Nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol.

Preparation XLII—5-nitro-2-trifluoromethylanisole

Cooled 140 mL pyridine in a large sealable vessel to −40° C. Bubbled intrifluoromethyl iodide from a gas cylinder which had been kept infreezer overnight. After adding ICF₂ for 20 min, added2-iodo-5-nitroanisole (24.63 g) and copper powder (67.25 g). Sealedvessel and stirred vigorously for 22 h at 140° C. After cooling to −50°C., carefully unsealed reaction vessel and poured onto ice and Et₂O.Repeatedly washed with Et₂O and H₂O. Allowed the ice-Et₂O mixture towarm to RT. Separated layers, washed organic layer with 1N HCl (3×),then brine, dried over Na₂SO₄, filtered and concentrated in vacuo.Eluted material through silica gel plug (4.5:1 Hex:CH₂Cl₂) to provide5-nitro-2-trifluoromethylanisole.

PreparationXLIII—1-[2-(5-nitro-2-trifluoromethylphenoxy)ethyl]pyrrolidine

1-[2-(5-Nitro-2-trifluoromethylphenoxy)ethyl]-pyrrolidine was preparedfrom 5-nitro-2-trifluoromethyl-phenol and 1-(2-chloroethyl)pyrrolidineby a procedure similar to that described for1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.

PreparationXLIV—1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine

1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine was preparedfrom 5-nitro-2-pentafluoroethylphenol and 1-(2-chloroethyl)piperidine bya procedure similar to that described in the preparation of1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.

PreparationXLV—3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenylamine

3-(2-Pyrrolidin-1-yl-methoxy)-4-trifluoromethyl-phenylamine was preparedfrom 1-[2-(5-nitro-2-trifluoromethylphenoxy)methyl]-pyrrolidine by aprocedure similar to that described in the preparation of1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine.

PreparationXLVI—2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide

2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamidewas prepared from3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenylamine and2-chloropyridine-3-carbonyl chloride by a procedure similar to thatdescribed in the preparation of1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.

Preparation XLVII—(R)Acetic acid2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethylester

Dissolved1-(5-nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol(3.5 g) in CH₂Cl₂ (15 ml), added TEA (2.55 ml) and cooled to 0° C.Acetyl chloride (781.3 μl) was added dropwise, forming a suspension. Themixture was warmed to RT and stirred for 1.5 h. Additional acetylchloride (200 μl) was added and the mix was stirred for another h. Themixture was diluted with CH₂Cl₂ and washed with sat. NaHCO₃. The organiclayer was removed, washed with brine and back extracted with CH₂Cl₂.Dried the combined organic layers over Na₂SO₄, filtered and concentratedin vacuo. The residue was purified over silica gel column (5:94.5:0.5MeOH: CH₂Cl₂:NH₄OH) to provide acetic acid2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethylester as a yellow brown oil.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) (R)Acetic acid    2-(5-amino-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-yl-methyl-ethyl    ester.-   b)    1-(2,2-Dimethyl-6-nitro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethanone.    M-NO₂ 206.4; Calc'd 250.1.

PreparationXLVIII—(R)2-Chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-nicotinamide

(R)Acetic acid2-{5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy}-1-pyrrolidin-1-yl-ethylester (408 mg) was dissolved in MeOH (15 ml) and NH₄OH (6 ml) was addedand the mixture was stirred at RT for 6 h. The reaction was concentratedin vacuo and dried under high vacuum. The residue was purified oversilica gel column (8:92:0.6 MeOH: CH₂Cl₂:NH₄OH). The purified fractionswere concentrated in vacuo and dried again to provide(R)-2-chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamideas a white foam.

PreparationXLIX—2-Dimethylamino-1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-ethanone

3,3-Dimethyl-6-nitro-2,3-dihydro-1H-indole (5 g) was dissolved in DMF(100 ml) and HOAt (3.89 g) dimethylamino-acetic acid (5.83 g) and EDC(3.89 g) were added. The reaction was stirred overnight. The mixture wasdiluted with CH₂Cl₂ (1 L) and washed with sat'd NaHCO₃ (3×200 ml). Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(SiO₂, EtOAc to 5% MeOH/EtOAc) to afford the title compound.

The following compounds were prepared similarly to the procedureoutlined above:

-   a)    1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone.

PreparationL—1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone

1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone(3.9 g) was dissolved in EtOH (30 ml) and Fe powder (3.1 g) NH₄Cl (299mg) and H₂O (5 ml) were added. The reaction was stirred at 80° C.overnight. The reaction was filtered through Celite® and evaporated offthe MeOH. The residue was partitioned between CH₂Cl₂ and sat'd NaHCO₂.The organic layer was removed, washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography (SiO₂, 25% EtOAc/hexane). The purified fractions wereconcentrated in vacuo to afford the compound as a white powder.

The following compounds were prepared similarly to the procedureoutlined above:

-   a)    1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-dimethylamino-ethanone.-   b)    3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-ylamine.-   c) 3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenylamine.    M+H 324.2. Calc'd 323.-   d)    3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-ylamine.    M+H 259.6; Calc'd 259.3.-   e)    3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-1,6-benzo[d]isothiazol-6-ylamine-   f) 1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-ylamine.-   g)    3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-ylamine.

PreparationLI—2-Boc-4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline

4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline (150 mg) wasdissolved with CH₂Cl₂ (3 ml) DIEA (100 ul) DMAP (208 mg and Boc₂O (204mg) and the mixture was stirred for 6 h at RT. The reaction was dilutedwith CH₂Cl₂, washed with sat'd NaHCO₃ and dried over MgSO₄, filtered andconcentrated to provide the compound which was used without furtherpurification.

The following compounds were prepared similarly to the procedureoutlined above substituting Ac₂O:

-   a)    1-(4,4-Dimethyl-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone.    M+H 249.3.

Preparation LII—2-Bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide

PMB-amine (5.35 ml) in CH₂Cl₂ (130 ml) was slowly added to2-bromo-5-nitro-benzoyl chloride (10.55 g) and NaHCO₃ (9.6 g) and themixture was stirred at RT for 1 h. The mixture was diluted with CH₂Cl₂(1 L), filtered, washed with dilute HCl, dried, filtered again,concentrated and dried under vacuum to provide the compound as a whitesolid. M+H 367. Calc'd 366.

PreparationLIII—2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide

To a suspension of NaH (1.22 g) in DMF (130 ml) was added2-bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide (6.2 g) in DMF (60 ml) at−78 C. The mixture was warmed to 0° C., 3-bromo-2-methyl-propene (4.57g) was added and the mixture was stirred for 2 h at 0° C. The reactionwas poured into ice water, extracted with EtOAc (2×400 ml), dried overMgSO₄, filtered and concentrated to a DMF solution which was usedwithout further purification.

Preparation LIV—of2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

2-Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide (23.4mmol) was dissolved in DMF (150 ml) and Et₄NC1 (4.25 g), HCO₂Na (1.75 g)and NaOAc (4.99 g) were added. N₂ was bubbled through the solution for10 min, then Pd(OAc)₂ (490 mg) was added and the mixture was stirredovernight at 70° C. The mixture was extracted with EtOAc, washed withsat'd NH₄Cl, dried over MgSO₄, filtered and concentrated until thecompound precipitated as a white solid.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 3,3-Dimethyl-6-nitro-2,3-dihydro-benzofuran was prepared from    1-bromo-2-(2-methyl-allyloxy)-4-nitro-benzene.-   b) 3,9,9-Trimethyl-6-nitro-4,9-dihydro-3H-3-aza-fluorene was    prepared from    4-[1-(2-bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine.

Preparation LV—4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one(2.0 g) was dissolved in CH₃CN (100 ml) and H₂O (50 ml) and cooled to 0°C. CAN (9.64 g) was added and the reaction was stirred at 0° C. for 30min, then warmed to RT and stirred for 6 h. The mixture was extractedwith CH₂Cl₂ (2×300 ml) washed with sat'd NH₄Cl, dried over MgSO₄,filtered and concentrated. The crude material was recrystallized inCH₂Cl₂/EtOAc (1:1) to give4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one as a white solid.

Preparation LVI—4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline

4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (230 mg) wasdissolved in THF (10 ml) and BH₃Me₂S (400 ul) was added and the reactionwas stirred overnight at RT. The reaction was quenched with MeOH (10 ml)and NaOH (200 mg) and heating at reflux for 20 min. The mixture wasextracted with EtOAc, washed with sat'd NH₄Cl, extracted with 10% HCl(20 ml). The acidic solution was treated with 5N NaOH (15 ml), extractedwith EtOAc (30 ml) dried, filtered and evaporated to give the compoundas a yellow solid. M+H 207.2, Calc'd 206.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 4-Boc-2,2-dimethyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine.

Preparation LVII—2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene

2-Methyl-4-nitro-1-pentafluoroethyl-benzene (2.55 g) was dissolved inCCl₄ (30 ml) and AIBN (164 mg) and NBS (1.96 g) were added. The reactionwas heated to reflux and stirred for 24 h. The mix was diluted withCH₂Cl₂, washed with sat'd NaHCO₂, dried over MgSO₄ and concentrated togive the compound as an oil which was used without further purification.

PreparationLVIII—1-Methyl-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine

2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.6 g) was added toN-methylpiperazine (5 ml) and stirred at RT for 3 h. The mixture wasfiltered and the filtrate was treated with 1-chlorobutane, extractedwith 2N HCl (100 ml). The acidic solution was treated with 5N NaOH (6ml) then extracted with EtOAc. The organic layer was removed, dried overMgSO₄ and concentrated to give the compound as an oil.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 4-(5-Nitro-2-pentafluoroethyl-benzyl)-morpholine.

Preparation LIX—1-Boc-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine

2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.5 g) was dissolvedin CH₂Cl₂ and added to N-Boc-piperazine (2.5 g) and NaHCO₃ (1 g) andstirred at RT overnight. The mixture was diluted with CH₂Cl₂ (100 ml),washed with sat'd NH₄Cl, dried over MgSO₄, filtered and concentrated.The residue was purified by silica gel chromatography (hexane,CH₂Cl₂:hexane 2:8) to give the compound as an yellow solid.

PreparationLX—(4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone

A mixture of 3-nitro-5-trifluoromethyl-benzoic acid (4.13 g),4-Boc-piperazine (2.97 g), EDC (3.88 g), HOBt (2.74 g), DIEA (3.33 ml)in CH₂Cl₂ (120 ml) was stirred at RT for 3 h. The mixture was dilutedwith CH₂Cl₂ (100 ml), washed with sat'd NH₄Cl, dried over MgSO₄,filtered and concentrated. The residue was purified by silica gelchromatography (hexane, CH₂Cl₂:hexane 1:2) to give the compound as awhite solid.

Preparation LXI—1-Boc-4-(3-nitro-5-trifluoromethyl-benzyl)-piperazine

(4-Boc-piperazin-1-yl)-(3-nitro-5-trifluoromethyl-phenyl)-methanone (403mg) was dissolved in THF (6 ml) and BH₃Me₂S (300 μl) was added and thereaction was stirred for 3 h at 60° C. and 2 h at RT. The reaction wasquenched with MeOH (5 ml) and NaOH (100 mg) and stirred at RT for 1 h.The mixture was concentrated and dissolved in CH₂Cl₂, washed with sat'dNH₄Cl/NaHCO₂, dried (MgSO₄), filtered and evaporated to give thecompound as an oil. M+H 390.3.

Preparation LXII—2-Ethyl-4-aminomethylpyridine

To a solution of 2-ethyl-4-thiopyridylamide (10 g) in MeOH (250 ml) wasadded Raney 2800 Nickel (5 g, Aldrich) in one portion. The mixture wasstirred at RT for 2 days then at 60° C. for 16 h. The mixture wasfiltered, concentrated to provide the desired compound.

PreparationLXIII—N-Boc-[2-(4-morpholin-4-yl-butyl)-pyrimidin-4-ylmethyl]-amine

N-Boc-(2-chloropyrimidine)-methylamine (663 mg) and4-(aminopropyl)morpholine (786 mg) were dissolved in MeOH andconcentrated in vacuo. The residue was heated at 100° C. for 15 min,forming a solid which was dissolved in CH₂Cl₂/MeOH then concentratedagain and heated 15 min more. Concentrated in vacuo and dried under highvacuum. Triturated with a small amount of IpOH and allowed to settleover a weekend. Filtered, rinsing with a small amount of IpOH to providethe compound as a white solid.

The following compounds were prepared similarly to the procedureoutlined above:

-   a)    (4-Bocaminomethyl-pyrimidin-2-yl)-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amine.    M+H 336.5; Calc'd 335.45.

Preparation LXIV—2-fluoronicotinic acid

In a flame dried 3-necked round bottom flask equipped with a droppingfunnel and thermometer, under N₂, THF (250 ml) was added via cannula.LDA (2M in cyclohexane, 54 ml) was added via cannula as the flask wascooled to −78° C. At −78° C., 2-fluoropyridine (8.87 ml) was addeddropwise over 10 min. The reaction was stirred for 3 h. Condensation wasblown off (with N₂) a few cubes of solid CO₂ and they were added to themixture. The mixture was warmed to RT once the solution turned yellow,and it was stirred overnight. The reaction was cooled to 0° C. and thepH was adjusted to ˜2.5 with 5N HCl. The mixture was concentrated invacuo and extracted with EtOAc. The EtOAc layer was washed with brine,dried over MgSO₄, filtered and concentrated to dryness. The resultingsolid was slurried in EtOAc (100 ml), filtered, washed with cold EtOAcand dried at 50° C. for 1 h to afford 2-fluoronictinic acid. M+H 142.1;Calc'd 141.0.

Preparation LXV—4-cyano-2-methoxypyridine

Under a stream of N₂ and with cooling, Na metal (2.7 g) was added toMeOH (36 ml) with a considerable exotherm. After the Na is dissolved, asolution of 2-chloro-4-cyanopyridine (15 g) in dioxane:MeOH (1:1, 110ml) was added via dropping funnel over a 10 min period. The reaction washeated to reflux for 3.5 h then cooled at ˜10° C. overnight. Solid wasfiltered off and the solid was washed with MeOH. The filtrate wasconcentrated to ˜60 ml and H₂O (60 ml) was added to redissolve aprecipitate. Upon further concentration, a precipitate formed which waswashed with H₂O. Further concentration produced additional solids. Thesolids were combined and dried in vacuo overnight at 35° C. to provide4-cyano-2-methoxypyridine which was used as is.

Preparation LXVI—(2-methoxypyridin-4-yl)methylamine

4-Cyano-2-methoxypyridine (1.7 g) was dissolved in MeOH (50 ml) andconc. HCl (4.96 ml) was added. Pd/C (10%) was added and H₂ was added andlet stand overnight. The solids were filtered through Celite® and thecake was washed with MeOH (˜250 ml). Concentration in vacuo produced anoil which was dissolved in MeOH (˜20 ml). Et₂O (200 ml) was added andstirred for 1 h. The resulting precipitate was filtered and washed withEt₂O to afford (2-methoxypyridin-4-yl)methylamine (hydrochloride salt)as an off-white solid.

Preparation LXVII—2-(4-Amino-phenyl)-2-methyl-propionic acid methylester

2-Methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.1 g) wasdissolved in THF (70 ml) and acetic acid (5 ml) and Zn (10 g) wereadded. The mixture was stirred for 1 h and filtered through Celite®. Thefiltrate was rinsed with EtOAc and the organics were evaporated to aresidue which was purified on silica gel chromatography (40%EtOAc/hexanes) to provide the desired compound as a yellow oil. M+H 194.

Preparation LXVIII—1-(2-tert-Butyl-phenyl)-4-methyl-piperazine

2-tert-Butyl-phenylamine and bis-(2-chloro-ethyl)-methylamine were mixedtogether with K₂CO₃ (25 g), NaI (10 g) and diglyme (250 mL) and heatedat 170° C. for 8 h. Cooled and filtered solid and evaporated solvent.Diluted with EtOAc, washed with NaHCO₃ solution, extracted twice morewith EtOAc, washed with brine, dried over Na₂SO₄ and evaporated to givethe compound as a dark solid.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 1-Bromo-2-(2-methyl-allyloxy)-4-nitro-benzene was prepared from    methallyl bromide.

Preparation LXIX3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenylamine

3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine(8.8 g, 0.032 mol) was added to trifluoro-methanesulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (7.91 g, 0.032 mol) and2N Na₂CO₃ aqueous solution (25 mL) was bubbled through N₂ for 5 min.Pd(PPh₃)₄ (3.7 g, 3.2 mmol) was added and the reaction was heated to 80°C. for 16 h. The reaction was cooled to RT and diluted with Et₂O (100mL). The mixture was filtered through Celite® and the filtrate waswashed with NaHCO₃ aqueous solution (25 ml) followed by brine (25 mL).The organic phase was dried over Na₂SO₄ and concentrated in vacuo. Thedesired product was isolated by passing through silica gel columnchromatography (EtOAc, then (2M NH₃) in MeOH/EtOAc) to provide a yellowoil.

Preparation LXX—3,3-Dimethyl-6-nitro-2,3-dihydro-benzo[d]isothiazole1,1-dioxide

3,3-Dimethyl-2,3-dihydro-benzo[d]isothiazole 1,1-dioxide was added toKNO₃ in H₂SO₄ cooled to 0° C. and stirred for 15 min. The reaction waswarmed to RT and stirred overnight. The mix was poured into ice andextracted with EtOAc (3×), washed with H₂O and brine, dried andevaporated to give the product which was used without furtherpurification.

The following compounds were prepared similarly to the procedureoutlined above:

-   a) 1,1,4,4-Tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene

PreparationLXXI—3-(1-Methyl-1,2,3,4-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenylamine

3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine(1.2 g) was added to trifluoro-methanesulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (1.0 g), LiCl (500 mg,Aldrich), PPh₃ (300 mg, Aldrich) and 2M Na₂CO₃ aqueous solution (6 ml)and was bubbled with N₂ for 5 min. Pd(PPH₃)₄ (300 mg, Aldrich) was addedand the reaction was heated to 80° C. for 16 h. The reaction was cooledto RT and diluted with Et₂O (100 mL). The mixture was filtered throughCelite® and the filtrate was washed with NaHCO₃ aqueous solution (25 ml)followed by brine (25 mL). The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The desired compound was isolated by silica gelcolumn chromatography (EtOAc 10% (2M NH₃) in MeOH/EtOAc) to provideyellow oil. M+H 257.2; Calc'd 256.1.

Preparation LXXII—Trifluoromethylsulfonic acid1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester

In a three-necked round bottom flask equipped with a thermometer and anadditional funnel was placed anhydrous THF (200 mL) and 2M LDA (82.8mL). The solution was cooled to −78° C. and a solution of1-methyl-piperidin-4-one (20 mL) in anhydrous THF (70 mL) was addeddrop-wise. The reaction was warmed to −10° C. over 30 min and cooleddown again to −78° C. Tf₂NPh (54.32 g) in 200 mL of anhydrous THF wasadded through the additional funnel over 30 min and anhydrous THF (30mL) was added to rinse the funnel. The reaction was warmed to RT and thereaction solution was concentrated in vacuo. The residue was dissolvedin Et₂O purified on neutral Al₂O₃ column chromatography (Et₂O aselutant). The product was obtained as orange oil. (20 g)

PreparationLXXIII—3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine

N₂ was bubbled through a solution of3-bromo-5-trifluoromethyl-phenylamine (2.38 g),5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (2.24 g, FrontierScientific) and KOAc (2.92 g), dppf (165 mg, Aldrich) in anhydrousdioxane (50 ml) for 2 min. PdCl₂ (dppf) (243 mg, Aldrich) was added andthe reaction was heated to 80° C. for 4 h. After cooling to RT, the mixwas diluted with 50 mL of Et₂O, filtered through Celite®, and thefiltrate was concentrated in vacuo. The residue was dissolved in Et₂O(100 mL), washed with sat. NaHCO₃ aqueous solution (50 mL) followed bybrine (50 mL). The organic phase was dried over Na₂SO₄ and concentratedin vacuo. The residue was dissolved in 3:2 Et₂O/Hex (100 mL), filteredthrough Celite® and the filtrate was concentrated in vacuo to afford adark brown semi-solid.

Preparation LXXIV—1-Boc-3-Hydroxymethyl-azetidine

A solution of 1-Boc-azetidine-3-carboxylic acid (1.6 g) and Et₃N (2 ml)in anhydrous THF (60 ml) was cooled to 0° C. Isopropyl chloroformate(1.3 g) was added via a syringe slowly; forming a white precipitatealmost immediately. The reaction was stirred for 1 h at 0° C. and theprecipitate was filtered out. The filtrate was cooled to 0° C. again andaqueous NaBH₄ solution (900 mg, 5 ml) was added via pipette and stirredfor 1 h. The reaction was quenched with NaHCO₃ solution (50 mL) and theproduct was extracted with EtOAc (200 mL). The organic phase was washedwith brine (50 mL), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was dissolved in EtOAc and passed through a short silica gelpad. Concentrating the filtrate in vacuo provided the compound as alight yellow oil.

PreparationLXXV—1-Boc-3-(3-nitro-5-trifluoromethyl-phenoxymethyl)-azetidine

A mixture of 1-Boc-3-methylsulfonyloxymethyl-azetidine (1.47 g),3-nitro-5-trifluoromethyl-phenol (1.15 g) and K₂CO₃ (1.15 g) in DMF (20ml) at 80° C. was stirred overnight. The reaction was cooled to RT anddiluted with 25 mL of sat. NaHCO₃ and 50 mL of EtOAc. The organic phasewas separated and washed with brine (25 mL), dried over Na₂SO₄ andconcentrated in vacuo. The crude compound was purified by columnchromatography (50% EtOAc/hex).

Preparation LXXVI—2,2-Dimethyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine

2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one was added to BH₃-THEcomplex (Aldrich) in THF with ice cooling. The mixture was heated toreflux for 2 h then carefully diluted with 12 mL of MeOH and heated toreflux for an additional 1 h. Concentrated HCl (12 mL) was added andheated to reflux for 1 h. The mixture was concentrated and the resultingsolid was suspended in a dilute aqueous solution of NaOH (1 M) andextracted with EtOAc (100 mL×4). The organic layers were washed with H₂Oand dried over MgSO₄. Evaporation of solvent gave a yellow solid.

Preparation LXXVII—2,2,4-Trimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one

2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (1.1 g) was mixed withMeI (850 mg, Aldrich), K₂CO₃ (1.38 g, Aldrich) and DMF (30 ml, Aldrich)at 40° C. for 48 h. The DMF was removed in vacuo and the residue wasdiluted with EtOAc (80 ml). The organic phase was washed with H₂O (50ml), aqueous Na₂SO₃ (50 ml) and brine (50 ml). The resulting solutionwas dried (MgSO₄) and concentrated to provide the compound which wasused as is.

PreparationLXXVIII—2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide

2-Amino-4-nitro-phenol (3.08 g, Aldrich) was stirred with THF (30 ml,Aldrich) in an ice bath. 2-Bromo-2-methyl-propionyl bromide (2.47 ml,Aldrich) and Et₃N (2.0 g, Aldrich) was slowly added via syringe. Themixture was stirred for 45 min then poured into ice. The aqueous phasewas extracted by EtOAc (50 mL×4). The organic layer was dried andconcentrated. The desired product was crystallized from EtOAc. (Chem.Pharm. Bull 1996, 44(1) 103-114).

Preparation LXXIX—2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one

2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide was mixedwith K₂CO₃ in 20 mL of DMF and stirred overnight at 50° C. The reactionmixture was poured into ice water. The precipitate was collected byfiltration and washed with H₂O. The crude compound was recrystallizedfrom EtOH.

PreparationLXXX—4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodide

1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-pyridinium (8 g) wasdissolved in glacial HOAc (10 ml) then diluted with H₂SO₄ (50 ml), thenNBS (3.8 g) was added. After 1 h, additional NBS (1.2 g) was added, 30min later another 0.5 g of NBS, then 15 min later 200 mg more NBS. After1 h, the mixture was neutralized with NH₄OH (conc.) with ice bathcooling. The neutralized mixture was then concentrated and used as is.

PreparationLXXXI—4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-1,2,3,6-tetrahydro-pyridine

4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodidewas mixed with MeOH (400 ml) and CH₂Cl₂ (200 ml), then treated withNaBH₄ (2.5 g) in portions. After stirring at RT for 2 h, the mixture wasextracted with CH₂Cl₂ (300 mL×3). The CH₂Cl₂ layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo, to provide thedesired product.

PreparationLXXXII—1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-pyridinium iodide

4-(4-Nitro-benzyl)-pyridine (4.3 g) was mixed with MeI (4 ml, 9.12g)/NaOH (5N, 30 ml), Bu₄NI (150 mg) and CH₂Cl₂ (50 ml) and stirred at RTovernight. Additional MeI (2 mL) was added along with 50 mL of NaOH(5N). 6 h later, more MeI (2 mL) was added. The mixture was stirred atRT over the weekend. The mixture was cooled on ice bath and the base wasneutralized by conc. HCl (aq) addition dropwise to pH 7. The compoundwas used as is.

PreparationLXXXIII—1-Methyl-4-(4-nitro-benzyl)-1,2,3,6-tetrahydro-pyridine

4-(4-Nitrobenzyl)pyridine (64 g) and TBAI (6 g) were dissolved in CH₂Cl₂(500 mL) and the solution was suspended with NaOH (aq. 5N, 450 mL) in a3 L 3-necked round bottom flask. With vigorous stirring, iodomethane(213 g) was added and stirred vigorously at RT for 60 h (or until bluecolor disappears). The reaction was quenched with dimethylamine (100 mL)and MeOH (300 mL) and stirred for 2 h. NaBH₄ (19 g) was added to themixture in small portions. The reaction mixture was stirred for 30 minat RT, then partitioned between CH₂Cl₂/H₂O (500 mL/500 mL). The organiclayer was collected and the aqueous layer was washed with CH₂Cl₂ (300mL×3). The combined organic layers was washed with brine thenconcentrated in vacuo. The residue was purified on a silica wash-column(7% TEA in EtOAc). The desired fractions were combined and concentratedunder vacuum to give the desired compound as a dark gray solid. (MS:M+1=261).

Preparation LXXXIV—1-Boc-4-formylpiperidine

4 A Molecular sieves were heated to 100° C. and a vacuum was applied.They were cooled to RT and purged with N2. CH₂Cl₂ (420 ml) and CH₃CN (40ml), NMO (40 g) and 1-Boc-4-hydroxymethylpiperidine (50 g) were addedand the mix was stirred for 5 min then cooled to 15° C. TPAP (4.1 g) isadded and an exotherm was observed. The reaction was maintained at RTwith external cooling. The reaction was stirred at RT for 3 h, filtered,concentrated, diluted with 50% EtOAc/hexanes and purified on a silicagel plug (50% EtOAc/hexanes). The eluant fractions were concentrated toafford a yellow oil.

Preparation LXXXV 2-Chloro-4-cyanopyridine

2-Chloro-4-cyanopyridine was prepared similar to the method described byDaves et al., J. Het. Chem., 1, 130-32 (1964).

Preparation LXXXVI 4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol

A mix of 1-(tert-butyl)-2-bromo-4-nitrobenzene (3.652 g), TEA (5.92 ml),3-buten-1-ol (5.48 ml), Pd(OAc)₂ (32 mg), Pd(PPh₃)₄ (327 mg) and toluene(40 ml) was degassed with nitrogen and heated in a sealed vessel for 16h at 120° C. The next day, the reaction mixture was cooled to RT,filtered, and concentrated in vacuo. The crude was eluted on a silicagel column with 15% to 22% EtOAc/hexanes gradient system to yield ayellow-brown oil.

Preparation LXXXVII 4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enal

4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol (1.024 g) was dissolved in10 ml of CH₂Cl₂ and added dropwise over 5 min to a −78 C mix of oxalylchloride (0.645 ml), DMSO (0.583 ml), and 10 ml CH₂Cl₂. The reaction wasstirred at −78 C for 1 h, then treated with a solution of TEA (1.52 ml)in 7 ml CH₂Cl₂ and stirred at −78 C for an additional 25 min, thenwarmed to −30° C. for 35 min. The reaction was treated with 50 ml ofsaturated aqueous NH₄Cl, diluted with H₂O and extracted with EtOAc. Theorganic layer was brine-washed, dried over Na₂SO₄, filtered, andconcentrated in vacuo to yield a yellow oil which was used as is inPreparation LXXXVIII.

Preparation LXXXVIII1-[4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine

4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enal (895 mg) was dissolved in 40ml THF, and to the solution was added pyrrolidine (0.317 ml). To thedeep orange solution was added NaBH(OAc)₃ (1.151 g) and glacial AcOH(0.207 ml). The reaction was stirred at RT overnight, then treated withsaturated aqueous NaHCO₃ and diluted with Et₂O and some 1N NaOH. Thelayers were separated, and the organic layer was extracted with aqueous2N HCl. The acidic aqueous layer was basified to pH>12 with 6 N NaOH,extracted with Et₂O, brine-washed, dried over Na₂SO₄, filtered, andconcentrated in vacuo to provide1-[4-(2-tert-butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine as aorange-brown oil.

Preparation LXXXVIV N-Boc-(2-chloropyrimidin-4-yl)-methylamine

To 2-chloropyrimidine-4-carbonitrile [2.5 g, prepared by the procedureof Daves et. al. [J. Het. Chem. 1964, 1, 130-132)] in EtOH (250 ml)under N₂ was added Boc₂O (7.3 g). After the mixture was briefly placedunder high vacuum and flushed with N₂, 10% Pd/C (219 mg) was added. H₂was bubbled though the mixture (using balloon pressure with a needleoutlet) as it stirred 4.2 h at RT. After filtration through Celite®,addition of 1.0 g additional Boc₂O, and concentration, the residue waspurified by silica gel chromatography (5:1→4:1 hexanes/EtOAc) to obtainN-Boc-(2-chloropyrimidin-4-yl)-methylamine.

Example 1

N-(4-Chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamideStep A—Preparation of3-[(tert-butoxy)carbonylamino]thiophene-2-carboxylic acid

To a mixture of methyl 3-amino-2-thiophenecarboxylate (8 g, 51 mmol) andBOC₂O (11 g, 50 mmol) in CH₂Cl₂ (400 ml) was added4-(dimethylamino)pyridine (1 g, 8.1 mmol).

The reaction was stirred at RT overnight and washed with 1N HCl (100ml), followed by water and brine. The organic layer was dried overNa₂SO₄ and evaporated under reduced pressure and used for the next stepwithout further purification. To the residue (2 g, ˜7 mmol) in EtOH (50ml) was added 1N NaOH (25 ml), the reaction was stirred at RT for 1 hand the solvent was evaporated under reduced pressure. Water (5 ml) wasadded and the solution was acidified with HOAc. The precipitate wasfiltered and used in the next step without further purification. MS(ES−): 242 (M−H)⁻.

Step B—Preparation of{3-[(tert-butoxy)carbonylamino](2-thienyl)}-N-(4-chlorophenyl)carboxamide

To a mixture of the thienyl carboxylic acid from Step A (300 mg, 1.23mmol) and 4-chloroaniline (160 mg, 1.25 mmol) and DIEA (300 μl, 1.6mmol) was added EDC (300 mg, 1.6 mmol) and HOBt (170 mg, 1.25 mmol) inCH₂Cl₂, the reaction was stirred at RT overnight. The solution waswashed with 1N HCl and saturated NaHCO₃, followed by H₂O and brine. Theorganic layer was dried over Na₂SO₄ and evaporated under reducedpressure and purified with preparative TLC to give the amide. MS (ES+):353 (M+H)⁺; (ES−): 351 (M−H)⁻.

Step C—Preparation ofN-(4-chlorophenyl){3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide

The amide from Step B was mixed with 25% TFA/CH₂Cl₂ and stirred at RTfor 1 h (monitored by HPLC). The solvent was evaporated under reducedpressure and the residue was mixed with 4-pyridine carboxaldehyde (260mg, 2.5 mmol) and NaCNBH₃ (160 mg, 2.5 mmol) in MeOH (40 ml). Thereaction was stirred at RT overnight and evaporated under reducedpressure. The final product was purified by prep-HPLC as TFA salt. MS(ES+): 344 (M+H)⁺; (ES−): 342 (M−H)⁻. Calc'd. for C₁₇H₁₄ClN₃OS—343.84.

Example 2

N-Phenyl{3-[(4-pyridylmethyl)amino](2-thienyl)}carboxamide

The title compound was analogously synthesized by method described inExample 1. The final product was purified by preparative HPLC as TFAsalt. MS (ES+): 310 (M+H)⁺; (ES−): 308 (M−H)⁻. Calc'd. forC₁₇H₁₅N₃OS—309.4.

Example 3

N-(4-Chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of (2-amino(3-pyridyl))-N-(4-chlorophenyl)carboxamide

To a mixture of 2-aminonicotinic acid (5.3 g, 38 mmol) and4-chloroaniline (4.9 g, 38 mmol) and DIEA (9 ml, 48 mmol) at 0° C. inCH₂Cl₂ was added EDC (9.5 g, 48 mmol) and HOBt (5.1 g, 38 mmol), thereaction was warmed to RT and stirred overnight. The solvent wasevaporated under reduced pressure and quenched with 2N NaOH solution (60ml) and stirred for 20 min. The precipitate was filtered to give thetitled compound. MS (ES+): 248 (M+H)⁺; (ES−): 246 (M−H)⁻.

Step B—Preparation ofN-(4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

To a mixture of the pyridyl carboxamide (400 mg, 1.6 mmol) from Step Aand 4-pyridinecarboxaldehyde (200 μl, 2 mmol) and HOAc (200 μl) inCH₂Cl₂ was added NaBH(OAc)₃ (600 mg, 2.8 mmol), the reaction was stirredat RT overnight. The reaction mixture was washed with H₂O and brine anddried over Na₂SO₄. The solution was evaporated and purified by prep-TLCto give the title compound. MS (ES+): 339 (M+H)⁺; (ES−): 337 (M−H)⁻.Calc'd for C₁₈H₁₅ClN₄O—338.796.

Example 4

N-(3,4-Dichlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide

The title compound was analogously synthesized by the method describedin Example 3. MS (ES+): 373 (M+H)⁺; (ES−): 370.9 (M−H)⁻. Calc'd forC₁₈H₁₄Cl₂N₄O—373.24.

Example 5

N-(3-Chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by the method describedin Example 3. MS (ES+): 339 (M+H)⁺; (ES−): 337 (M−H)⁻. Calc'd. forC₁₈H₁₅ClN₄O—338.1.

Example 6

N-(4-Chlorophenyl){3-[(4-pyridylmethyl)amino](2-pyridyl)}carboxamide

The title compound was analogously synthesized by method described inExample 3. MS (ES+): 339 (M+H)⁺; (ES−): 337 (M−H)⁻. Calc'd. forC₁₈H₁₅ClN₄O—338.8

Example 7

N-(4-Chlorophenyl){3-[(6-quinolylmethyl)amino](2-pyridyl)}carboxamide

The title compound was analogously synthesized by the method describedin Example 3. MS (ES+): 389 (M+H)⁺; (ES−): 387 (M−H)⁻. Calc'd. forC₂₂H₁₇ClN₄O—388.86.

Example 8

N-(3,4-Dichlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}-carboxamide

The title compound was analogously synthesized by the method describedin Example 3. MS (ES+): 423 (M+H)⁺; (ES−): 421 (M−H)⁻. Calc'd. forC₂₂H₁₆Cl₂N₄O—423.30.

Example 9

N-(4-Chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of6-methyl-2-[(4-pyridylmethyl)amino]pyridine-3-carboxylic acid

The mixture of 2-chloro-6-methyl-nicotinic acid (1.0 eq.) and4-aminomethyl-pyridine (2.0 eq.) was stirred in a sealed tube at 130° C.overnight. The resulted mixture was cooled to RT, diluted with CH₂Cl₂,filtered to collected the brown solid. The brown solid wasrecrystallized in ethanol to give the substituted amine as light brownsolid. MS (ES+): 244 (M+H)⁺.

Step B—Preparation ofN-(4-chlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide

To the mixture of the substituted amine from Step A (1.0 eq.) and4-chloroaniline (2.0 eq) in CH₂Cl₂ was addedbis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.1 eq.) and TEA (1.1eq.). The mixture was stirred overnight, diluted with CH₂Cl₂, washedwith saturated NH₄Cl solution, dried over Na₂SO₄, filtered andconcentrated, purified by flash chromatography (4% MeOH/CH₂Cl₂) to givethe title compound as an white solid. MS (ES+): 353 (M+H); (ES−): 351(M−H). Calc'd. for C₁₉H₁₇ClN₄O—352.82.

Example 10

N-(3,4-Dichlorophenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by the method describedin Example 9. MS (ES+): 387 (M+H); (ES−): 385 (M−H). Calc'd. forC₁₉H₁₆Cl₂N₄O—387.27.

Example 11

N-(3-Fluoro-4-methylphenyl){6-methyl-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by the method describedin Example 9. MS (ES+): 351 (M+H); (ES−): 349 (M−H). Calc'd. forC₂₀H₁₉FN₄O—350.39.

Example 12

{6-Chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(4-pyridylmethyl)carboxamide

The title compound was analogously synthesized by the method describedin Example 9. MS (ES+): 354 (M+H); (ES−): 352 (M−H). Calc'd. forC₁₈H₁₆ClN₅O—353.81.

Example 13

N-(3,4-Dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by the method describedin Example 9. MS (ES+): 409 (M+H). Calc'd. for C₁₈H₁₉Cl₃N₄O—407.7.

Example 14

N-(4-Chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by method described inExample 9. MS (ES+): 374 (M+H); (ES−): 372 (M−H). Calc'd. forC₁₈H₁₄Cl₂N₄O—373.24.

Example 15

{6-Chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(3-fluorophenyl)carboxamide

The title compound was analogously synthesized by the method describedin Example 9. MS (ES+): 357 (M+H); (ES−): 355 (M−H). Calc'd. forC₁₈H₁₉FN₄OCl—356.5.

Example 16

N-(3-Chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by the method describedin Example 9. MS (ES+): 374 (M+H); (ES−): 372 (M−H). Calc'd. forC₁₈H₁₄Cl₂N₄O—373.24.

Example 17

N-(4-Chlorophenyl){3-[(4-pyridylmethylene)amino](4-pyridinecarboxamide

A mixture of (2-amino(4-pyridyl))-N-(4-chlorophenyl)carboxamide (350 mg,1.4 mmol) (similar procedure to Example 3, Step A) and 4-pyridinecarboxaldehyde (200 μl, 2 mmol) and 4-toluenesulfonic acid monohydrate(50 mg) in EtOH (50 ml) was heated to reflux overnight. The solvent wasevaporated and the residue was purified by prep-TLC. MS (ES+): 337(M+H)⁺; (ES−): 335 (M−H)⁻. Calc'd. for C₁₈H₁₃ClN₄O—336.8.

Example 18

N-(4-Chlorophenyl){3-[(4-pyridylmethyl)amino](4-pyridyl)}carboxamide

The compound from Example 17 was mixed with NaBH₄ (100 mg) in EtOH (20ml) and heated to reflux for 5 min. The solvent was evaporated underreduced pressure and the residue was purified by prep-TLC to give thetitled compound. MS (ES+): 339 (M+H)⁺; (ES−): 337 (M−H)⁻. Calc'd. forC₁₈H₁₅ClN₄O—338.8.

Example 19

N-(3-Fluoro-4-methylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by the method in Examples17-18. MS (ES−): 337 (M−H)⁻. Calc'd. for C₁₉H₁₇FN₄O—336.37.

Example 20

N-(4-Chlorophenyl){2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by the method describedin Examples 17-18. MS (ES+): 389 (M+H)⁺; (ES−): 387 (M−H)⁻. Calc'd. forC₂₂H₁₇ClN₄O—388.86.

Example 21

N-(4-Chlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}carboxamide

The title compound was analogously synthesized by the method describedin Examples 17-18. MS (ES+): 389 (M+H)⁺; (ES−): 387 (M−H)⁻. Calc'd. forC₂₂H₁₇ClN₄O—388.86.

Example 22

N-(4-Chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamideStep A—Preparation of 5-bromo-2-hydroxynicotinic acid

A solution of sodium hypobromide was made by adding Br₂ (1.01 ml, 39.5mmol, 1.1 eq) slowly over a period of 5 min to NaOH (5N, 40 ml) that waspreviously cooled to 0° C. in an ice bath. The solution was stirred for10 min before adding 2-hydroxynicotinic acid (5.0 g, 35.9 mmol) andplaced in a 50° C. oil bath and stirred. Concurrently, a second pot ofsodium hypobromide solution was made by slowly adding Br₂ (1.01 ml, 39.5mmol, 1.1 eq) to a NaOH solution (5N, 40 ml) in an ice bath. The secondpot of sodium hypobromide was added to the solution of2-hydroxynicotinic acid after 24 h of heating then was stirred for anadditional 24 h. The solution was cooled to RT, placed in an ice bathand acidified with concentrated HCl while stirring. The precipitatewhich formed was filtered, washed and dried to afford the desiredcompound as an off-white solid.

Step B—Preparation of 5-bromo-2-chloronicotinic acid

A solution of 5-bromo-2-hydroxynicotinic acid, from Step A (8.3 g, 38.1mmol) and SOCl₂ (40 ml) in a 150 ml round bottom flask was placed in an80° C. oil bath and stirred while adding 10 ml of DMF. The solution washeated at reflux for 4 h at 80° C. before cooling to RT. Excess SOCl₂was stripped off under reduced pressure forming a yellow-brown residue.The yellow-brown residue was placed in an ice bath and cooled to 0° C.Residual SOCl₂ was neutralized and the chloro compound was precipitatedby the dropwise addition of water. Precipitate was filtered, washed anddried to afford the desired chloro compound as a light yellow solid.

Step C—Preparation of 5-bromo-2-chloro-N-(4-chlorophenyl)nicotinamide

To a mixture of 4-chloroanaline (594 mg, 4.7 mmol, 1. eq.), EDC (1.62 g,8.5 mmol, 2 eq.), HOBT (572 mg, 4.2 mmol, 1 eq.), and DIEA (1.1 ml, 6.3mmol, 1.5 eq.) in CH₂Cl₂ (50 ml) was added 5-bromo-2-chloronicotinicacid from Step B (1.0 g, 4.2 mmol). The reaction was stirred at RTovernight. The solution was quenched with water and the organic layerwas purified by chromatography (50% EtOAc in hexane) to afford alight-yellow compound. MS (ES+): 347.0, 349.0 (M+H)⁺; (ES−): 345.0,347.0 (M−H)⁻.

Step D—Preparation of5-(3-thiophene)-2-chloro-N-(4-chlorophenyl)nicotinamide

3-Thiophene boronic acid (204 mg, 1.6 mmol, 1.1 eq), Pd(OAc)₂ (33 mg,0.2 mmol, 0.2 eq.), and K₂CO₃ (505 mg, 4.3 mmol, 3 eq.) were added to asolution of 5-bromo-2-chloro-N-(4-chlorophenyl)nicotinamide from Step C(500 mg, 1.4 mmol) in DMF (20 ml). The reaction was placed in a 50° C.oil bath and stirred overnight. The reaction was filtered and purifiedby medium pressure chromatography (30% EtOAc in hexane) to afford thedesired thienyl compound as an off white solid.

Step E—Preparation ofN-(4-chlorophenyl){2-[(4-pyridylethyl)amino]-5-(3-thienyl)-(3-pyridyl)}carboxamide

4-(Aminoethyl)pyridine (10 ml) was added to a 25 ml round-bottom flaskcontaining 5-(3-thiophene)-2-chloro-N-(4-chlorophenyl)nicotinamide fromStep D (200 mg, 0.6 mmol). The solution was placed in an 80° C. oil bathand stirred overnight. The reaction was cooled to RT, and after anaqueous work-up, was purified by medium-pressure chromatography (80%EtOAc in hexane) to afford the title compound as a light yellow solid.MS: (ES+) 435.1 (M+H); (ES−) 432.8 (M−H). Calc'd. forC₂₃H₁₉ClN₄OS—434.95.

Example 23

N-(4-Chlorophenyl){5-(4-methoxyphenyl)-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide

The title compound was prepared analogously to Example 22. MS: (ES+)445.1 (M+H). Calc'd. for C₂₅H₂₄ClN₄O—444.92.

Example 24

N-(4-Chlorophenyl){5-bromo-2-[(4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide

The title compound was prepared analogously to Example 22, Steps A, B, Cand E. MS: (ES+) 419 (M+H) (ES−) 417 (M−H). Calc'd. forC₁₈H₁₄BrClN₄O—417.69.

Example 25

N-(4-Isopropylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A: Preparation of(2-chloro-3-pyridyl)-N-(4-isopropylphenyl)carboxamide

To a mixture of 2-chloronicotinic acid (6.3 g) and 4-isopropylaniline(5.26 ml) and DIEA (10 ml) in CH₂Cl₂ (200 ml) was added EDC (10 g) andHOBt (5.4 g). The reaction was stirred at RT overnight and washed with 2N NaOH (100 ml), H₂O (250 ml) and brine (100 ml). The organic layer wasdried over Na₂SO₄ and evaporated to give(2-chloro-3-pyridyl)-N-(4-isopropylphenyl)-carboxamide.

Step B: Preparation ofN-[4-(isopropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride

A mixture of (2-chloro(3-pyridyl))-N-(4-isopropylphenyl)carboxamide (1.5g, from Step A) and 4-aminomethylpyridine (0.71 ml) was heated at 130°C. neat for 3 h. The reaction was cooled and diluted with CH₂Cl₂ andwashed with H₂O twice followed by brine. The organic layer was driedwith Na₂SO₄ and evaporated under reduced pressure. The residue waspurified by column chromatography with EtOAc and further mixed with MeOHand 1 N HCl/Et₂O (2 ml). The solution was evaporated to furnish thetitled compound. MS (ES+): 347 (M+H)⁺; (ES−): 345 (M−H). Calc'd. forC₂₁H₂₂N₄O—346.18.

The following compounds (Examples 26-81) were synthesized by the methoddescribed in Example 25 unless specifically described. Detailedintermediate preparations are included.

TABLE 1

# Y R¹ R² M + H calc'd 26 —NH—CH₂—

H 347 346.2 27 NH—CH₂—

H 356 355.1 28 NH—CH₂—

H 471 470.1 29 NH—CH₂—

H 352 351.4 30 NH—CH₂—

H 365 364.2 31 NH—CH₂—

H 368 367.5 32 NH—CH₂—

H 369 368.5 33 NH—CH₂—

H 377 376.2 34 NH—CH₂—

H 366.8 366.8 35 NH—CH₂—

5-Br 447.0 445.7 36 NH—CH₂—

H 425.0 424.5 37 NH—CH₂—

H 363.2 362.4 38 NH—CH₂—

H 393.2 392.4 39 NH—CH₂—

H 393.2 392.4 40 NH—CH₂—

H 350.8 350.4 41 NH—CH₂—

H 389.2 388.5 42 NH—CH₂—

H 351.0 350.4 43 NH—CH₂—

H 367.1 366.8 44 NH—CH₂—

H 401.3 400.4 45 NH—CH₂—

H 377.2 376.5 46 NH—CH₂—

H 361.4 360.4 47 NH—CH₂—

H 377.1 376.4 48 NH—CH₂—

H 347.1 346.4 49 NH—CH₂—

H 349.1 348.4 50 NH—CH₂—

H 393.2 392.4 51 NH—CH₂—

H 411.2 411.3 52 NH—CH₂—

H 403.1 401.3 53 NH—CH₂—

H 415.2 414.4 54 NH—CH₂—

H 393.2 392.4 55 NH—CH₂—

H 403.2 401.3 56 NH—CH₂—

H 351.0 350.4 57 NH—CH₂—

H 369.1 366.8 58 NH—CH₂—

H 412.3 411.5 59 NH—CH₂—

H 338.8 338.4 60 NH—CH₂—

H 334.1 333.4 61 NH—CH₂—

H 333.6 333.4 62 NH—CH₂—

H 333.6 333.4 63 NH—CH₂—

H 361.1 360.4 64 NH—CH₂—

H 379.0 378.4 65 NH—CH₂—

H 399 398.9 66 NH—CH₂—

H 522.3 521

Example 67

{5-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide

{6-Chloro-5-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(methylethyl)phenyl]carboxamide(50 mg, 0.125 mmol, from Example 66) dissolved in EtOH (10 mL) with TEA(0.5 mL) and suspended with Pd/C (10%, 5 mg). The mixture was stirred atRT under a H₂ balloon for 45 min. The mixture was filtered through alayer of Celite® and the filtrate was concentrated in vacuo. The residuewas partitioned between CH₂Cl₂ and aq. NaHCO₃ (sat.). The organicsolution was dried over Na₂SO₄ and concentrated in vacuo to give thetitle compound. MS: 365 (M+1). Calc'd. for C₂₁H₂₁FN₄O—364.42.

Example 68

2-[(Pyridin-4-ylmethyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl](3-pyridyl)carboxamideStep A Preparation of 2-bromo-1-tert-butyl-4-nitrobenzene

NBS (125.0 g, 697.5 mmol) was slowly added to a solution of TFA:H₂SO₄(5:1, 750 mL) and tert-butyl-4-nitrobenzene (100.0 g, 558.0 mmol) at RT.The solution was stirred for 24 h then poured over 5 kg of ice. Theresulting suspension was filtered and washed with a 1:1 MeOH:H₂Osolution (200 mL) and dried in a vacuum oven. MS (ES+): 258.1, 260.1(M+H)⁺. Calc'd for C₁₀H₁₂BrNO₂: 257.01.

Step B Preparation of 4-(2-tert-butyl-5-nitrophenyl)pyridine

To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (8.6 g, 33.3 mmol)and toluene (70 mL) in a 150 mL round bottom flask, 4-pyridylboronicacid (4.5 g, 36.6 mmol), Pd(PPh₃)₄ (3.8 g, 3.3 mmol) and K₂CO₃ (13.8 g,99.9 mmol) were added. The solution was stirred for 24 h at 80° C.before cooling to RT. The solution was filtered through a pad of Celite®and purified by silica flash chromatography (30% EtOAc/Hexanes). Thisafforded the desired compound as a yellow solid. MS (ES+): 257.2 (M+H)⁺;(ES−): 255.2 (M−H)⁻. Calc'd for C₁₅H₁₆N₂O₂: 256.12.

Step C Preparation of 4-(2-tert-butyl-5-nitrophenyl)-1-methylpyridinium

4-(2-tert-Butyl-5-nitrophenyl)pyridine (2.0 g, 7.8 mmol, Step B) wasadded to a round-bottom flask and dissolved in EtOH (10 mL). MeI (30 mL)was added and the flask was placed in an 80° C. sand bath and heated toreflux. After 6 h the solution was cooled to RT and the excess MeI andEtOH was concentrated in vacuo resulting in the desired compound as alight brown solid. MS (ES+): 271.2 (M+H)⁺; (ES−): 269.2 (M−H)⁻. Calc'dfor C₁₆H₁₉N₂O₂ ⁺: 271.14.

Step D Preparation of4-tert-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

4-(2-tert-Butyl-5-nitrophenyl)-1-methylpyridinium (2.1 g, 7.8 mmol, StepC) was added to a 100 mL round-bottom flask and dissolved in a 10%H₂O/EtOH mixture. To the flask iron dust (1.31 g, 23.4 mmol) and NH₄Cl(460 mg, 8.6 mmol) were added. The flask was placed in a 100° C. sandbath and heated to reflux. After 2 h the solution was cooled to RT andfiltered through a pad of Celite®. The resulting solution wasconcentrated in vacuo to a yellow solid and re-dissolved in MeOH (20 mL,anhydrous). The solution was cooled to 0° C. by placing it in an icebath and slowly adding NaBH₄ (450 mg, 11.7 mmol). After addition of theNaBH₄, the solution was cooled to RT and stirred for 30 min. The solventwas concentrated in vacuo and the solid was re-dissolved in CH₂Cl₂ andfiltered. The solution was again concentrated in vacuo to afford anamorphous clear yellow solid. MS (ES+): 245.2 (M+H)⁺. Calc'd forC₁₆H₂₄N₂: 244.19.

Step E Preparation of2-[(pyridin-4-ylmethyl)amino]-N-[4-tert-butyl-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl](3-pyridyl)carboxamide

The titled compound was prepared from4-tert-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline (Step D)by the method described in Example 25. MS: (ES+) 456.3 (M+H); (ES−)454.4 (M−H). Calc'd for C₂₈H₃₃N₅O—455.59.

Example 69

N-(3,4-Dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

A mixture ofN-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide(18 mg, 0.044 mmol, made from 2,6-dichloronicotinic acid) and2-morpholin-4-ylethylamine (300 μL) was stirred at 80° C. for 20 h. Thereaction mixture was purified on silica gel chromatography to yieldN-(3,4-dichlorophenyl){6-[(2-morpholin-4-ylethyl)amino]-2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide.MS (ES+): 501 (M+H)⁺; (ES−): 499 (M−H)⁻. Calc'd forC₂₄H₂₆Cl₂N₆O₂—500.15.

Example 70

N-[4-(Morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A Preparation of 4-[(4-nitrophenyl)methyl]morpholine

A mixture of nitrobenzyl bromide (648 mg, 3.0 mmol) and morpholine (522mg, 6.0 mmol) in CH₂Cl₂ was stirred for 5 h at RT. Filtration to removethe white solid, and the filtrate was concentrated to give4-[(4-nitrophenyl)-methyl]morpholine as a solid, which was used in nextstep without further purification.

Step B Preparation of 4-(morpholin-4-ylmethyl)phenylamine

A mixture of 4-[(4-nitrophenyl)methyl]morpholine (220 mg, 1.0 mmol, StepA), iron powder (279 mg, 5.0 mmol) and NH₄Cl (39 mg, 0.7 mmol) in EtOH(3 mL) and H₂O (3 mL) was stirred for 4 h at 80° C. Filtration andconcentration gave the crude 4-(morpholin-4-ylmethyl)-phenylamine, whichwas used in next step without further purification.

Step C Preparation ofN-[4-(morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from4-(morpholin-4-ylmethyl)phenylamine (Step B) by the method described inExample 25. MS (ES+): 404 (M+H); (ES−): 402 (M−H). Calc'd. forC₂₂H₂₄N₄O₂—403.20.

Example 71

N-(4-{2-[(tert-Butoxy)carbonylamino]ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A Preparation of(tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]carboxamide

A mixture of 2-(4-nitrophenyl)ethylamine (1.01 g, 5.0 mmol), anddi-tert-butyl dicarbonate (1.09 g, 5.0 mmol) in CH₂Cl₂ (20 mL) and 1NNaOH (20 mL) was stirred for 20 h at RT. The mixture was extracted withCH₂Cl₂, washed with brine, and dried with MgSO₄. Filtration andconcentration yielded(tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]carboxamide, which was used innext step without further purification.

Step B Preparation of N-[2-(4-aminophenyl)ethyl](tert-butoxy)carboxamide

A mixture of (tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]-carboxamide (570mg, 2.15 mmol, Step A), iron powder (602 mg, 10.75 mmol) and NH₄Cl (82mg, 1.5 mmol) in EtOH (6 mL) and H₂O (6 ml) was stirred for 4 h at 80°C. Filtration and concentration gave the crude compound, which was usedin next step without further purification.

Step C Preparation ofN-[4-(morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared fromN-[2-(4-aminophenyl)ethyl](tert-butoxy)carboxamide (Step B) by themethod described in Example 25. MS (ES+): 448 (M+H); (ES−): 446 (M−H).Calc'd. for C₂₅H₂₉N₅O₃—447.23.

Example 72

N-[4-(2-Aminoethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

To the solution ofN-(4-{2-[(tert-butoxy)carbonylamino]-ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide(96 mg, 0.22 mmol, Example 71) in CH₂Cl₂ (3 mL) was added TFA (3 mL).The mixture was stirred for 3 h at RT. The reaction mixture wasconcentrated and dried in vacuo to yieldN-[4-(2-aminoethyl)phenyl]{2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide.MS (ES+): 348 (M+H); (ES−): 346 (M−H). Calc'd. for C₂₀H₂₁N₅O—347.17.

The following compounds (Example a-m) were synthesized by the methoddescribed above, unless specifically described.

-   a)    N-[3-(azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.-   b)    2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide.    M+H 512.3; Calc'd 511.7.-   c)    N-[3-(piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 485.3.-   d)    N-[3-(piperazine-1-methyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 521.4.-   c)    N-[3-(piperazine-1-methyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 471.2; Calc'd 470.-   d)    N-[1-(2-Amino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]nicotinamide.    M+H 461.1.-   e)    N-[1-(2-Amino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]nicotinamide.    M+H 431.4.-   f)    (S)N-[3-(pyrrolidin-2-yl-methoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 522.6; Calc'd 521.5.-   g)    (R)N-[3-(pyrrolidin-2-yl-methoxy)-4-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 472.6; Calc'd 471.5.-   h)    (R)N-[3-(pyrrolidin-2-yl-methoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 522.3; Calc'd 521.5.-   i)    (S)N-[3-(pyrrolidin-2-yl-methoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-yl-methyl)-amino]-nicotinamide.    M+H 472; Calc'd 471.5.-   j)    (S)N-[3-(4-piperidinyloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 472; Calc'd 471.5.-   k)    2-[(2-Methoxy-pyridin-4-yl-methyl)-amino]-N-[3-(piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide.-   l)    N-{4-tert-Butyl-3-[2-(piperidin-4-yl)-methoxy]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 474.-   m)    N-[4-tert-Butyl-3-(pyrrolidin-2-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 460.-   n)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.-   o)    N-(3,3-Dimethyl-1-pyrrolidin-2-ylmethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.

Example 73

N-[4-(tert-Butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS (ES+): 406 (M+H); (ES−): 405 (M−H). Calc'd. for C₂₂H₂₃N₅O₃—405.18.

Example 74

N-[3-Amino-4-(tert-butyl)phenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide

A mixture ofN-[4-(tert-butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide(100 mg, 0.25 mmol, Example 73), iron powder (69 mg, 1.25 mmol) andNH₄Cl (10 mg, 0.17 mmol) in EtOH (0.5 mL) and H₂O (0.5 ml) was stirredfor 4 h at 80° C. The reaction mixture was filtered, concentrated, andpurified through column chromatography to give the product. MS (ES+):376M+H); (ES−):374 (M−H). Calc'd. for C₂₂H₂₅N₅O—375.21.

Example 75

N-[4-(Isopropyl)phenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS (ES+): 347 (M+H); (ES−): 345 (M−H). Calc'd. for C₂₁H₂₂N₄O—346.18.

Example 76

N-(3-Aminosulfonyl-4-chlorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS (ES+): 418 (M+H); (ES−): 416 (M−H). Calc'd. for C₁₈H₁₆N₅O₃S—417.07.

Example 77

N-{3-[(4-Methylpiperazinyl)sulfonyl]phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A Preparation of 3-[(4-methylpiperazinyl)sulfonyl]-1-nitrobenzene

A mixture of 3-nitrobenzenesulfonyl chloride (664 mg, 3.0 mmol) andmethylpiperazine (600 mg, 6.0 mmol) in EtOH was stirred for 2 h at RT.The reaction was concentrated and triturated in Et₂O to yield ayellowish solid, 3-[(4-methylpiperazinyl)sulfonyl]-1-nitrobenzene, andwas used in next step without further purification.

Step B Preparation of 3-[(4-methylpiperazinyl)sulfonyl]phenylamine

3-[(4-Methylpiperazinyl)sulfonyl]phenylamine was analogously synthesizedfrom 3-[(4-methylpiperazinyl) sulfonyl]-1-nitrobenzene (Step A) by themethod described in Example 74, which was used in next step withoutfurther purification. MS (ES+): 256 (M+H). Calc'd. forC₁₁H₁₇N₃O₂S—255.10.

Step C Preparation ofN-[4-(morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from3-[(4-methylpiperazinyl)sulfonyl]phenylamine (Step B) by the methoddescribed in Example 25. MS (ES+): 467 (M+H); (ES−): 465 (M−H). Calc'd.for C₂₃H₂₆N₆O₃S—466.18.

Example 78

N-[4-(1,1,2,2,2-Pentafluoroethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A Preparation of 4-(1,1,2,2,2-pentafluoroethyl)phenylamine

1-Nitro-4-(1,1,2,2,2-pentafluoroethyl)benzene was synthesized by themethod described in the reference [John N. Freskos, SyntheticCommunications, 18(9), 965-972 (1988)]. It was reduced with Fe similarto that described in Example 74. It was used in next step withoutfurther purification.

Step B Preparation ofN-[4-(1,1,2,2,2-Pentafluoroethyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from4-(1,1,2,2,2-pentafluoroethyl)phenylamine (Step A) by the methoddescribed in Example 25. MS (ES+): 423 (M+H); (ES−): 421 (M−H). Calc'd.for C₂₀H₁₅FN₄O—422.12.

Example 79

N-[4-(1,1,2,2,3,3,4,4,4-Nonafluorobutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A Preparation of 4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenylamine

The title intermediate was analogously synthesized by the methoddescribed of W. A. Gregory, et al. [J. Med. Chem., 1990, 33, 2569-2578].1-nitro-4-(1,1,2,2,3,3,4,4-monofluorobutyl)benzene was reduced with Fedescribed in Example 68, Step D, and used in next step without furtherpurification.

Step B Preparation ofN-[4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)phenylamine (Step A) by the methoddescribed in Example 25. MS (ES+): 523 (M+H); (ES−): 521 (M−H). Calc'd.for C₂₂H₁₅F₉N₄O—522.37.

Example 80

N-[4-(Isopropyl)phenyl]{2-[(2-(1,2,4-triazolyl)ethyl)amino](3-pyridyl)}carboxamideStep A Preparation of 2-(1,2,4-triazolyl)ethylamine

A mixture of (tert-butoxy)-N-(2-chloroethyl)-carboxamide (900 mg, 5mmol), 1,2,4-triazole (690 mg, 10 mmol) and Na₂CO₃ (1.06 g, 10 mmol) inDMF (3 mL) was stirred overnight at 100° C. The mixture was filtered andconcentrated to give an oil. The oil was treated with TFA (10 mL) andstirred for 3 h. The reaction was concentrated to give the titledintermediate, which was used in next step without further purification.

Step B Preparation ofN-[4-(methylethyl)phenyl]{2-[(2-(1,2,4-triazolyl)ethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from 2-(1,2,4-triazolyl)ethylamine(Step A) by the method described in Example 25. MS (ES+): 351 (M+H);(ES−): 349 (M−H). Calc'd. for C₁₉H₂₂N₆O—350.19.

Example 81

(2-{[2-(2-Pyridylamino)ethyl]amino}(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamideStep A Preparation of 2-(2-pyridylamino)ethylamine

Ethylenediamine (6 g, 0.1 mol) and 2-fluoropyridine (10 g, 0.1 mol) wereheated neat at 120° C. overnight. The reaction was cooled and theresidue was used in next step without further purification.

Step B Preparation of(2-{[2-(2-pyridylamino)ethyl]amino}-(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

The titled compound was prepared from 2-(2-pyridylamino)ethylamine (StepA) by the method described in Example 25. MS (ES+): 402 (M+H); (ES−):400 (M−H). Calc'd. for C₂₀H₁₈F₃N₅O—401.15.

Example 82

2-[(Pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-nicotinamideStep A: Preparation of(2-chloro(3-pyridyl))-N-(3-trifluoromethylphenyl)carboxamide

2-Chloropyridine-3-carbonyl chloride (18.02 g, 0.102 mol) in CH₂Cl₂ (100ml) was added dropwise (via an addition funnel) to a stirred solution of3-(trifluoromethyl)-aniline (15.00 g, 0.093 mol) and DIEA (24.39 ml,0.14 mol) in CH₂Cl₂ (500 ml) at 0° C. The mixture gradually was warmedto RT. The reaction continued for 18 h before washing several times withsaturated NaHCO₃ aqueous solution and brine, respectively. The organiclayer was dried over Na₂SO₄ and evaporated. The resulting oil waspurified over silica gel with EtOAc/hexane (2:1) as eluant to leave theamide as a white solid (26.08 g). MS: (ES+) 301 (M+1)⁺; (ES−): 299(M−1)⁻. Calc'd for C₁₃H₈ClF₃N₂O: 300.03.

Step B: Preparation of N-[3-trifluoromethylphenylphenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide hydrochloride

The amide (10.0 g 0.033 mol, Step A) and 4-aminomethylpyridine (10.81 g,0.10 mol) were combined and heated at 120° C. for 4 h. After cooling toRT, the residue was dissolved in EtOAc and washed several times withsaturated NaHCO₃ aqueous solution and brine, respectively. The organiclayer was dried over Na₂SO₄ and evaporated. The crude yellow oil waspurified over silica gel with EtOAc as eluant to leave an amber oil(10.9 g). The free base was dissolved in MeOH (20 ml) and treated with aHCl ethereal solution (1.0 eq.). The solvent was evaporated to leave thesalt as a white solid. The HCl salt was dried in vacuo at 30° C. for 24h. MS: (ES+) 373 (M+1)⁺; (ES−): 371 (M−1)⁻. Calc'd. forC₁₉H₁₅P₃N₄O—372.12.

The following compounds (Examples 83-138) were analogously synthesizedby the method described in Example 82 unless specifically described.Detailed intermediate preparations are included.

TABLE 2

# Y R¹ R² M + H calc'd  83 —NH—CH₂—

H 356 355.14  84 —NH—CH₂—

H 431 430.12  85 —NH—CH₂—

H 359 358.1  86 —NH—CH₂—

H 355 354.15  87 —NH—CH₂—

H 359 358.18  88 —NH—CH₂—

H 349 348.128  89 —NH—CH₂—

H 355 354.15  90 —NH—CH₂—

H 395 394.18  91 —NH—CH₂—

H 339 338.12  92 —NH—CH₂—

H 339 338.12  93 —NH—CH₂—

H 345 344.16  94 —NH—CH₂—

H 361 360.20  95 —NH—CH₂—

H 361 360.20  96 —NH—CH₂—

H 319 318.5  97 —NH—CH₂—

H 389 388.11  98 —NH—CH₂—

H 333 332.16  99 —NH—CH₂—

H 361 360.2 100 —NH—CH₂—

H 431 430 101 —NH—CH₂—

H 349 348.16 102 —NH—CH₂—

H 333 332.16 103 —NH—CH₂—

H 457 456.18 104 —NH—CH₂—

H 381 380.16 105 —NH—CH₂—

H 395 394.18 106 —NH—CH₂—

H 334 333.16 107 —NH—CH₂—

H 348 347.17 108 —NH—CH₂—

H 362 361.19 109 —NH—CH₂—

H 321 320.13 110 —NH—CH₂—

H 348 347.17 111 —NH—CH₂—

H 441 440.11 112 —NH—CH₂—

H 407 406.08 113 —NH—CH₂—

H 353 352.11 114 —NH—CH₂—

H 383 382.11 115 —NH—CH₂—

H 388 387.43 116 —NH—CH₂—

H 346 345.00 117 —NH—CH₂—

H 344 343.38 118 —NH—CH₂—

H 344 343.38 119 —NH—CH₂—

H 344 343.38 120 —NH—CH₂—

H 351 350.43 121 —NH—CH₂—

H 371 370.43

Example 122

N-(4-Phenoxyphenyl){2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}carboxamide

MS: 411 (M+1); 409 (M−1). Calc'd. for C₂₅H₂₂N₄O₂—410.17.

Example 123

2-[(Benzo[b]thiophen-3-ylmethyl)amino](3-pyridyl)}-N-(4-phenoxyphenyl)carboxamide

MS: (ES+) 452 (M+1)⁺; (ES−): 450 (M−1)⁻. Calc'd. for C₂₇H₂₁N₃O₂S—451.14.

Example 124

N-{2-[2-(Dimethylamino)ethoxy]-5-(tert-butyl)phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of{2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl}dimethylamine

To a mixture of 2-nitro-4-tert-butylphenol (2 g) andN,N-dimethylethanolamine (1.3 g) and PPh₃ (4 g) in THF (50 ml) was addedDEAD (2.6 ml). The reaction was stirred at RT for 1 h, diluted withEtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer wasbasified with NaHCO₃, extracted with EtOAc twice and washed with H₂O andbrine. The organic layer was dried over Na₂SO₄ and evaporated to give{2-[4-(tert-butyl)-2-nitrophenoxy]-ethyl}dimethylamine, was used in nextstep without further purification.

Step B—Preparation of{2-[4-(tert-butyl)-2-aminophenoxy]-ethyl}dimethylamine

{2-[4-(tert-Butyl)-2-nitrophenoxy]-ethyl}dimethylamine (Step A) washydrogenated under H₂ atmosphere to give{2-[4-(tert-butyl)-2-aminophenoxy]-ethyl}dimethylamine, and used in nextstep without further purification.

Step C—Preparation ofN-{2-[2-(dimethylamino)ethoxy]-5-(tert-butyl)phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from{2-[4-(tert-butyl)-2-aminophenoxy]-ethyl}dimethylamine (Step B) by themethod described in Example 82. MS (ES+): 448 (M+H); (ES−): 446 (M−H).Calc'd. for C₂₆H₃₃N₅O₂—447.26.

Example 125

N-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of 1-[2-(tert-butylphenyl]-4-methylpiperazine

A mixture of 2-tert-butylaniline (5.4 g) andN-methylbis(2-chloroethyl)amine hydrochloride (7 g) and K₂CO₃ (5 g) inNaI (2 g) in diglyme (150 ml) was heated at 170° C. for 8 h. Thereaction was filtered and the filtrate was evaporated under high vacuum.The residue was mixed with EtOAc (200 ml) and H₂O (200 ml) and extractedwith EtOAc twice. The combined organic layer was washed with brine,dried over Na₂SO₄ and evaporated to give crude1-[2-(tert-butylphenyl]-4-methyl-piperazine, which was used in next stepwithout further purification.

Step B—Preparation of1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine

The crude 1-[2-(tert-butylphenyl]-4-methylpiperazine (260 mg, Step A)was stirred with H₂SO₄ (3 ml) at 0° C. and HNO₃ (1.2 ml) was slowlyadded to the reaction. The reaction was warmed to RT, stirred for 30min. and poured on ice and basified with K₂CO₃ slowly. The solution wasextracted with EtOAc three times, washed with H₂O, followed by brine,dried over Na₂SO₄, and evaporated under reduced pressure. The residuewas purified by column chromatography to give1-[2-(tert-butyl)-5-nitrophenyl]-4-methylpiperazine (260 mg), which washydrogenated under H₂ atmosphere to give1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine.

Step C—Preparation ofN-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine (Step B) by themethod described in Example 82. MS (ES+): 459 (M+H); (ES−): 457 (M−H).Calc'd. for C₂₇H₃₄N₆O—458.28.

Example 126

N-[3-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of 3-(4-methylpiperazinyl)phenylamine

The intermediate was analogously synthesized from 3-nitroaniline by themethod described in Example 130.

Step B—Preparation ofN-[3-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from 3-(4-methylpiperazinyl)phenylamine(Step A) by the method described in Example 82. MS (ES+): 403 (M+H);(ES−): 401 (M−H). Calc'd. for C₂₃H₂₆N₆O—402.22.

Example 127

N-[4-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}formamideStep A—Preparation of 4-methyl-1-(4-nitrophenyl)piperazine

1-Fluoro-4-nitrobenzene (3.0 g, 0.021 mol) and 1-methylpiperazine (6.98ml, 0.63 mol) were combined and heated neat at 90° C. for 48 h. Uponcooling to RT, the resulting brown oil solidified. The crude materialwas purified by re-crystallization from EtOAc/Hexane mixtures to leavethe title compound as an orange solid (3.59 g). MS: (ES+) 222 (M+1)⁺;(ES−): 220 (M−1)⁻. Calc'd for C₁₁H₁₅N₃O₂: 221.12.

Step B—Preparation of 4-methyl-1-(4-aminophenyl)piperazine

4-Methyl-1-(4-nitrophenyl)piperazine (2.0 g, 9 mmol, Step A) and 10%Pd/C (200 mg) were added to EtOH/MeOH (1:1) (50 ml) at RT. The reactionstirred under a H₂ atmosphere (via balloon) overnight. The mixture wasfiltered through a plug of Celite® and the filtrate was concentratedunder reduced pressure to leave the desired material as a light yellowoil. The material was used in subsequent reaction without purification.MS: (ES+) 192 (M+1)⁺; (ES−): 190 (M−1)⁻. Calc'd for C₁₁H₁₂N₃: 191.14.

Step C Preparation ofN-[4-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}formamide

The titled compound was prepared from4-methyl-1-(4-aminophenyl)piperazine (Step B) by the method described inExample 82. MS (ES+): 403 (M+H); (ES−): 401 (M−H). Calc'd. forC₂₃H₂₆N₆O—402.22.

Example 128

N-[1-(1-Methyl-(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of 1-(1-methyl(4-piperidyl))-6-nitroindoline

6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane,N-methyl-4-piperidone (5 g) was added to the mixture, followed by 12 gNaBH(OAc)₃ and 1 mL of glacial AcOH. The mixture was stirred at RTovernight. Saturated NaHCO₃ solution (200 mL) was added to the reactionmixture and stirred for 1 h. The resulting mixture was separated byseparation funnel, the organic layer was extracted once with saturatedNaHCO₃ solution and once with brine. The resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 2:1 EtOAc:MeOHto afford an orange oil. MS: 262 (M+1). Calc'd. for C₁₄H₁₉N₃O₂—261.32.

Step B—Preparation of 1-(1-methyl-4-piperidyl)indoline-6-ylamine

1-(1-Methyl(4-piperidyl))-6-nitroindoline (3 g, Step A) was dissolved in100 mL MeOH, and the mixture was bubbled with N₂ for 10 min. 10% Pd/C(200 mg) was added and the mixture was stirred under H₂ overnight. Themixture was filtered through Celite® and concentrated in vacuo to afforda light yellow oil. MS: 232 (M+1). Calc'd. for C₁₄H₂₁N₃—231.34.

Step C—Preparation ofN-[1-(1-methyl(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from1-(1-methyl-4-piperidyl)indoline-6-ylamine (Step B) by the methoddescribed in Example 82. MS: 443 (M+1). Calc'd. for C₂₆H₃₀N₆O—442.56.

Example 129

N-[1-(1-Methyl-(4-piperidyl))indolin-6-yl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide

MS: 457 (M+1). Calc'd. for C₂₇H₃₂N₆O—456.58.

Example 130

N-[1-(2-Piperidylethyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of 1-(6-nitroindolinyl)-2-piperidylethan-1-one

6-Nitroindoline (2.5 g) was dissolved in 200 mL of CH₂Cl₂, followed byDIEA (2.5 g). The mixture was cooled down to 0° C. in ice bath.Chloroacetyl chloride (1.7 g) in 20 mL CH₂Cl₂ was added dropwise to themixture over 10 min and the mixture was stirred at RT overnight. Themixture was extracted once with saturated NaHCO₃ solution and once withbrine, the resulting organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel with 3:2 Hexane:EtOAc to afford a yellowoil (1.4 g) which was added to piperidine (5 mL), followed by NaI (100mg). The mixture was heated at 70° C. overnight then concentrated invacuo and extracted between EtOAc and saturated NaHCO₃ solution, theorganic layer was washed with brine, the resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 9:1 EtOAc:MeOHto afford a yellow oil. MS: 290 (M+1). Calc'd. for C₁₅H₁₉N₃O₃—289.33.

Step B—Preparation of 1-(2-piperidylethyl)indoline-6-ylamine

1-(6-Nitroindolinyl)-2-piperidylethan-1-one (1.6 g, Step A) wasdissolved in 100 mL MeOH, the mixture was bubbled with N₂ for 10 min.10% Pd/C (200 mg) was added and the mixture was stirred under H₂overnight. The mixture was filtered through Celite® and concentrated invacuo to afford a yellow solid. 400 mg was dissolved in 20 mL anhydrousTHF, 5 mL borane-THF (1 M) solution was added dropwise and the mixturewas stirred at RT overnight. The mixture was quenched with MeOH, 100 mgNaOH added and heated at 70° C. for 30 min. The resulting mixture wasconcentrated in vacuo and extracted between EtOAc and saturated NaHCO₃solution, the organic layer was washed with brine, the resulting organiclayer was dried over MgSO₄, filtered and concentrated in vacuo to afforda yellow oil. MS: 246 (M+1). Calc'd. for C₁₅H₂₃N₃—246.36.

Step C—Preparation ofN-[1-(2-piperidylethyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from1-(2-piperidylethyl)indoline-6-ylamine (Step B) by the method describedin Example 82. MS: 457 (M+1). Calc'd. for C₂₇H₃₂N₆O—456.58.

Example 131

N-[1-(2-Piperidylacetyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS: 471 (M+1). Calc'd. for C₂₇H₃₀N₆O₂—470.57.

Example 132

N-[3,3-Dimethyl-1-(1-methyl(piperid-4-yl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of N-(2-bromo-5-nitrophenyl)acetamide

2-Bromo-5-nitroaniline (10 g) was dissolved in 500 mL of CH₂Cl₂, DIEA(6.6 g) was added to the mixture, followed by DMAP (100 mg). The mixturewas cooled to 0° C. in ice bath. Acetyl chloride (4 g in 50 mL CH₂Cl₂)was added dropwise to the reaction mixture. After the mixture wasstirred at RT over 3 h, extracted once with saturated NaHCO₃ solutionand once with brine, the resulting organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel with 1:1 EtOAc:Hexane to 100% EtOActo afford N-(2-bromo-5-nitrophenyl)acetamide as a white solid. MS: 258(M−1). Calc'd. for C₈H₂BrN₂O₂—259.06.

Step B—Preparation ofN-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide

A suspension of 2 g NaH (95% powder) in anhydrous DMF (100 mL) wascooled to −78° C., N-(2-bromo-5-nitrophenyl)acetamide (7 g, Step A) indry DMF (50 mL) was added to the mixture under N₂ atmosphere. After themixture was warmed to 0° C., 3-bromo-2-methylpropene (7.3 g in 20 dryDMF) was added to the mixture. The mixture was stirred at RT overnight.Next morning, the mixture was poured into a container of ice andextracted between saturated NaHCO₃ solution and EtOAc. The resultingorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The crude material was purified by flash chromatography on silica gelwith 7:2 hexane:EtOAc to afford the title compound as a yellow gum. MS:314 (M+1). Calc'd. for C₁₂H₁₃BrN₂O₂—313.15.

Step C—Preparation of1-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone

N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide (4.5 g, StepB) was dissolved in anhydrous DMF (50 mL), tetraethyl-ammonium chloride(2.5 g), sodium formate (1.2 g), NaOAc (3 g) were added, and theresulting mixture was bubbled with N₂ gas for 10 min. Pd(OAc)₂ (350 mg)was added and the mixture was heated at 80° C. under N₂ atmosphereovernight. After the mixture was concentrated in vacuo, it waspartitioned between saturated NaHCO₃ solution and EtOAc, the resultingorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The crude material was purified by flash chromatography on silica gelwith 2:1 Hexane:EtOAc to afford the title compound as a yellow gum. MS:235 (M+1). Calc'd. for C₁₂H₁₄N₂O₃—234.25.

Step D—Preparation of 3,3-dimethyl-6-nitroindoline

1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone (1.8 g, Step C)was dissolved in EtOH (50 mL), 12N HCl (50 mL) was added and theresulting mixture was heated at 70° C. overnight. After the mixture wasconcentrated in vacuo, it was partitioned between saturated NaHCO₃solution and EtOAc, the resulting organic layer was dried over MgSO₄,filtered and concentrated in vacuo to afford a yellow solid. MS: 193(M+1). Calc'd. for C₁₀H₁₂N₂O₂—192.21.

Step E—Preparation of3,3-dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indole

3,3-Dimethyl-6-nitroindoline (0.8 g) was dissolved in CH₂Cl₂ (50 mL),N-methyl-4-piperidone (1 g) was added to the mixture, followed by 2.5 gNaBH(OAc)₃ and glacial AcOH (1 mL). The mixture was stirred at RTovernight. Saturated NaHCO₃ solution (50 ml) was added to the reactionmixture and stirred for 1 h. The resulting mixture was separated byseparation funnel, the organic layer was extracted once with saturatedNaHCO₃ solution and once with brine, the resulting organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 9:1 EtOAc:MeOHto afford the title compound as an orange oil. MS: 290 (M+1). Calc'd.for C₁₆H₂₃N₃O₂—289.37.

Step F—Preparation of3,3-dimethyl-1-(1-methyl(4-piperidyl))indoline-6-ylamine

3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-6-nitro-2,3-dihydro-1H-indole(600 mg, Step E) was dissolved in MeOH (20 mL), the mixture was bubbledwith H₂ for 10 min. 10% Pd/C (100 mg) was added and the mixture wasstirred under H₂ overnight. The mixture was filtered through Celite® andconcentrated in vacuo to afford the title compound as an oil. MS: 260(M+1). Calc'd. for C₁₆H₂₅N₃—259.39.

Step G—Preparation ofN-[3,3-dimethyl-1-(1-methyl(4-piperidyl))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from3,3-dimethyl-1-(1-methyl(4-piperidyl))indoline-6-ylamine (Step E) by themethod described in Example 82. MS: 471 (M+1). Calc'd. forC₂₈H₃₄N₆O—470.61.

Example 133

N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of 1-acetyl-6-amino-3,3-dimethylindoline

1-Acetyl-3,3-dimethyl-6-nitroindoline (250 mg) was dissolved in MeOH (20mL), the mixture was bubbled with H₂ for 10 min. 10% Pd/C (50 mg) wasadded and the mixture was stirred under H₂ overnight. The mixture wasfiltered through Celite® and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel with 1:1 EtOAc:CH₂Cl₂to afford the title compound as a white crystalline material. MS: 205(M+1). Calc'd. for C₁₂H₁₆N₂O—204.27.

Step B—Preparation ofN-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from1-acetyl-6-amino-3,3-dimethylindoline (Step A) by the method describedin Example 82.

Step C—Preparation ofN-(3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared fromN-(1-acetyl-3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide(Step B) by the deacylation method described in Example 993. MS: 374(M+1). Calc'd. for C₂₂H₂₃N₅O—373.45.

Example 134

N-[3-(1-Methyl-(4-piperidyl))indol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole

5-Nitroindole (2.6 g) was dissolved in anhydrous MeOH (100 ml), followedby N-methyl-4-piperidone (5 g) and NaOMe powder (5 g). The mixture washeated to reflux under N₂ overnight. The mixture was concentrated invacuo. The crude was partitioned between saturated NaHCO₃ solution andEtOAc, the resulting organic layer was dried over MgSO₄, filtered andconcentrated in vacuo to afford a yellow solid. This solid was washedwith EtOAc (5 mL) and MeOH (2 ml) to afford the title compound as abright yellow solid. MS: 258 (M+1). Calc'd. for C₁₄H₁₅N₃O₂—257.29.

Step B—Preparation of 3-(1-methyl-4-piperidyl)indole-5-ylamine

3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-nitro-1H-indole (2.7 g,Step A) was dissolved in MeOH (50 mL), the mixture was bubbled with H₂for 10 min. 10% Pd/C (150 mg) was added and the mixture was stirredunder H₂ overnight. The mixture was filtered through Celite® andconcentrated in vacuo to afford 3-(1-methyl-4-piperidyl)indole-5-ylamineas a yellow oil. MS: 230 (M+1). Calc'd. for C₁₄H₁₉N₃—229.32.

Step C—Preparation ofN-[3-(1-methyl-(4-piperidyl))indol-5-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from3-(1-methyl-4-piperidyl)indole-5-ylamine (Step B) by the methoddescribed in Example 82. MS: 441 (M+1). Calc'd. for C₂₆H₂₈N₆O—440.54.

Example 135

N-[4-(1,1-Dimethyl-3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of methyl 2-methyl-2-(4-nitrophenyl)propionate

To a stirred solution of 2-(4-nitrophenyl)-propionic acid (9 g, 46 mmol)in MeOH (300 mL) was added HCl (4M in dioxane, 11.5 mL, 46 mmol). Themixture was stirred at RT overnight and quenched with aqueous NaHCO₃.The mixture was extracted with EtOAc. The organic layer was dried overMgSO₄, evaporated under reduced pressure and to the partial residue at0° C. in THF (100 mL) was added NaH (1.66 g, 41.5 mmol). The mixture wasstirred at RT for 1 h and MeI (2.58 g, 41.5 mmol) was added. Thereaction was stirred at RT overnight and was quenched with H₂O. Themixture was extracted with EtOAc, the organic layer was dried overMgSO₄, evaporated under reduced pressure to give the title compoundwhich was used in the next step without further purification. Calc'd forC₁₁H₁₃NO₄: 223.08.

Step B—Preparation of 2-methyl-2-(4-nitro-phenyl)-propan-1-ol

To a stirred solution of methyl 2-methyl-2-(4-nitrophenyl)propionate(5.32 g, 23.8 mmol, Step A) in THF (200 mL) at 0° C. was added asolution of BH₃ 1M in THF (25.8 mL, 45.8 mmol). The reaction was stirredat RT overnight and quenched with MeOH. THF was evaporated under reducedpressure and the residue was diluted in EtOAc and aqueous 1M HCl wasadded. The mixture was extracted with EtOAc, the organic layer was driedover MgSO₄ and evaporated under reduced pressure. The product waspurified by flash chromatography using 40% EtOAc-hexane to give thetitle compound as a yellow solid.

Step C—Preparation of 2-methyl-2-(4-nitro-phenyl)-propionaldehyde

To a stirred solution of the alcohol (2.08 g, 10.8 mmol, Step B) at 0°C. in CH₂Cl₂ was added NMO (1.9 g, 16.1 mmol), molecular sieves 4 Å andTPAP (76 mg, 0.2 mmol). The reaction was stirred for 1 h and wasfiltered on silica pad. Solvent was evaporated under reduced pressure.Crude aldehyde was used without further purification in the next step.

Step D—Preparation of 3-methyl-3-(4-nitrophenyl)butan-1-aldehyde

To a suspension of methoxymethyltriphenyl-phosphonium chloride (6.4 g,18.6 mmol) in THF (150 mL) was added a solution of KHMDS 0.5 M intoluene (37 mL, 18.5 mmol). The mixture was stirred for 30 min and crudealdehyde (Step C) was added. The reaction was stirred at RT for 1 h andquenched with H₂O. Mixture was extracted with EtOAc, dried andevaporated under reduced pressure. Et₂O was added and the formedprecipitate was filtered on silica pad (rinsed with 40% EtOAc-hexane).The solvent was removed and crude product was dissolved in CH₂Cl₂. Asolution of TFA-H₂O (1:1, 10 mL) was added and the reaction was stirredfor 2 h at RT. Aqueous NaHCO₃ was added until pH 7 and residue wasextracted with CH₂Cl₂. Organic layer was dried, filtered and evaporated.Crude compound was purified by flash chromatography (40% EtOAc-hexane)to give the title compound as a yellow oil. Calc'd for C₁₁H₁₃NO₃:207.09.

Step E—Preparation of 4-[3-methyl-3-(4-nitro-phenyl)-butyl]-morpholine

To a stirred solution of 3-methyl-3-(4-nitrophenyl)butan-1-aldehyde (509mg, 2.4 mmol, Step D) and morpholine (0.21 mL, 2.4 mmol) in THF (30 mL)was added NaBH(OAc)₃ (0.73 g, 3.4 mmol). The mixture was stirred at RTovernight and was washed with 1M HCl. CH₂Cl₂ was added and the layerswere separated. The aqueous layer was basified to pH 9 using 1M NaOH andextracted with CH₂Cl₂. This organic layer was dried and evaporatedyielding the morpholino compound. Calc'd for C₁₅H₂₂N₂O₃: 278.16.

Step F Preparation of 4-(1,1-dimethyl-3-morpholin-4-ylpropyl)phenylamine

To a solution of 4-[3-methyl-3-(4-nitro-phenyl)-butyl]-morpholine (0.50g, 1.8 mmol, Step E) in THF (40 mL) was added AcOH (1.97 mmol, 34.5mmol) followed by zinc (9.1 g, 137 mmol). The mixture was stirred for 1h and filtered on Celite®. The mixture was diluted with H₂O, and aqueousNaHCO₃ and the THF was evaporated. The residue was extracted with EtOAc,dried and evaporated to give the title intermediate. Calc'd forC₁₅H₂₄N₂O: 248.19.

Step G—Preparation ofN-[4-(1,1-dimethyl-3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from4-(1,1-dimethyl-3-morpholin-4-ylpropyl)phenylamine (Step F) by themethod described in Example 82. MS: 460.0 (M+1). Calc'd. forC₂₇H₃₃N₅O₂—459.60.

Example 136

N-[4-(tert-Butyl)phenyl]{2-[({2-[(1-methyl(4-piperidyl))-methoxy](4-pyridyl)}methyl)amino](3-pyridyl)}carboxamideStep A—Preparation of 4-hydroxymethyl-1-methylpiperidine

To a solution of 4-piperidylmethanol (1.0 g, 8.7 mmol) and HCHO (2 mL,25 mmol, 37% in H₂O) in CH₃CN was added NaCNBH₃ (0.5 g, 12.5 mmol). Theresulting mixture was stirred for 1 h and filtered. The filtrate wasconcentrated and the residue was distilled (105° C., 40 torr) to givethe title intermediate.

Step B—Preparation of{2-[(1-methyl-4-piperidyl)methoxy]-4-pyridyl}methylamine

To a suspension of NaH (0.44 g, 12.7 mmol, 60% in mineral oil) in DMF(25 mL) was added a solution of alcohol (1.1 g, 8.5 mmol, Step A) in 3mL of DMF. After 20 min, a solution of 2-chloro-4-cyanopyridine (1.2 g,8.5 mmol) in 2 mL of DMF was added. The resulting mixture was stirredfor 2 h, diluted with CH₂Cl₂, and washed with H₂O twice. The organiclayer was dried over Na₂SO₄ and concentrated to give2-[(1-methyl-4-piperidyl)methoxy]pyridine-4-carbonitrile, which washydrogenated under regular conditions to furnish the title intermediate.MS (ES+): 236 (M+H)⁺. Calc'd C₁₃H₂₁N₃O—235.33.

Step C—Preparation ofN-[4-(tert-butyl)phenyl]{2-[({2-[(1-methyl(4-piperidyl))-methoxy](4-pyridyl)}methyl)amino](3-pyridyl)}carboxamide

The title compound was prepared from{2-[(1-methyl-4-piperidyl)methoxy]-4-pyridyl}methylamine (Step B) by themethod described in Example 82. MS (ES+): 488 (M+H)⁺; (ES−): 486 (M−H)⁻.Calc'd C₂₉H₃₇N₅O₂—487.64.

Example 137

N-(4-Bromo-2-fluorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS (ES+): 402 (M+H)⁺; (ES−): 400. Calc'd C₁₈H₁₄BrFN₄O—401.238.

Example 138

N-[4-(tert-Butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide

MS (ES+): 395 (M+H)⁺; (ES−): 393 (M−H)⁻. Calc'd C₂₂H₂₃ClN₄O—394.90.

Example 139

{2-[({2-[3-(Dimethylamino)prop-1-ynyl](4-pyridyl)}methyl)amino](3-pyridyl)}-N-[4-(tert-butyl)phenyl]carboxamide

A mixture ofN-[4-(tert-butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide(0.15 g, 0.38 mmol, Example 139), 1-dimethylamino-2-propyne (62 mg, 0.76mmol), PdCl₂(PPh₃)₂ (13 mg, 0.0019 mmol) and CuI (7 mg, 0.019 mmol) in 1mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resultingmixture was filtered over Celite®. The filtrate was concentrated, andthe residue was purified by prep-HPLC (reverse phase) to give the titlecompound. MS (ES+): 442 (M+H)⁺; (ES−): 440 (M−H)⁻. Calc'dC₂₇H₃₁N₅O—441.58.

Example 140

(2-{[(2-Methoxy(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamideStep A—Preparation of (2-methoxy-4-pyridyl)methylamine

A solution of 2-methoxyisonicotinylcarboxamide (1.0 g, 6.5 mmol) andBH₃-THF complex (35 mmol) in 35 mL of THF was stirred at RT for 16 h.The reaction was quenched by addition of MeOH, and the resulting mixturewas concentrated. The residue was diluted with 1N aq. NaOH and CH₂Cl₂.The organic layer was separated, dried over Na₂SO₄, and concentrated.

Step B—Preparation of(2-{[(2-methoxy(4-pyridyl))methyl]-amino}(3-pyridyl))-N-[4-(methylethyl)phenyl]carboxamide

The title compound was prepared from (2-methoxy-4-pyridyl)methylamine(Step A) by the method described in Example 82. MS (ES+): 377 (M+H)⁺;(ES−): 375 (M−H)⁻. Calc'd C₂₂H₂₄N₄O₂—376.46.

Example 141

N-{3-[3-(Dimethylamino)propyl]-5-(trifluoromethyl)phenyl}-{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of{3-[3-amino-5-(trifluoromethyl)phenyl]propyn-2-yl}dimethylamine

A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol),1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl₂(PPh₃)₂ (0.26 g,0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at100° C. in a sealed tube for 3 h. The resulting mixture was filteredover Celite®. The filtrate was concentrated, and the residue waspurified by prep-HPLC (reverse phase) to give the titled compound. MS(ES+): 243 (M+H)⁺; (ES−): 241 (M−H)⁻. Calc'd C₁₂H₁₃F₃N₂—242.24.

Step B—Preparation of{3-[3-amino-5-(trifluoromethyl)phenyl]propyl}dimethylamine

A mixture of the propynyl-aniline (7 g, 29 mmol, Step A) and Pd(OH)₂(0.5 g) in MeOH (250 mL) was stirred under 50 psi H₂. After 2 h, theresulting mixture was filtered over Celite®. The filtrate wasconcentrated, and the residue was diluted with aq. 1N HCl. The aq. layerwas washed with Et₂O, made basic with aq. 5N NaOH, and extracted withCH₂Cl₂. The organic solution was dried over NaSO₄ and concentrated togive the titled compound. MS (ES+): 386 (M+H)⁺; (ES−): 384 (M−H)⁻.Calc'd C₁₈H₁₉ClF₃N₃O—385.81.

Step C—Preparation ofN-{3-[3-(dimethylamino)propyl]-5-(trifluoromethyl)phenyl}-{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was prepared by the method described in Example 82.MS (ES+): 458 (M+H)⁺; (ES−): 456 (M−H)⁻. Calc'd C₂₄H₂₆F₃N₅O—457.497.

Example 142

N-[4-(tert-Butyl)-3-(3-piperidylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of 1-piperidylprop-2-en-1-one

To a 0° C. solution of acryloyl chloride (4.576 g, 50.558 mmol) in 50 mlof CH₂Cl₂ was added dropwise and very carefully piperidine (4.305 g,50.558 mmol). The reaction flask was vented during the exothermicaddition. After the addition was completed, the white slurry was stirredat 0° C. for 40 min and at RT for 1 h. The reaction was diluted with 70ml CH₂Cl₂ and washed first with about 60 ml 2N HCl and then with about60 ml of a mix of 2N NaOH and brine. The organic layer was dried overNa₂SO₄. The solution was evaporated by heating in a H₂O bath at 60° C.without vacuum. Once most solvent had been evaporated off, it wasfurthered dried to a clear oil under high vacuum at RT for 30 min.

Step B—Preparation of 1-bromo-2-(tert-butyl)-5-nitrophenyl

Br₂ (17.4 ml) was added dropwise over 40 min to a stirred mixture of4-tert-butylnitrobenzene (59.5 g, 332 mmol), AgSO₄ (56.5 g, 181 mmol),H₂SO₄ (300 ml), and H₂O (33 ml) at RT. The mixture was stirred for 3 h,then poured into 0.1 M Na₂S₂O₅/H₂O (1 L). The solid was filtered, washedwith H₂O, Et₂O, and CH₂Cl₂. The filtrate layers were separated. Theaqueous fraction was extracted with Et₂O. The combined organic layerswere combined, dried over Na₂SO₄, and concentrated in vacuo. The yellowsolid was triturated with hexanes to give a pale yellow crystallinesolid.

Step C—Preparation of(2E)-3-[2-(tert-butyl)-5-nitrophenyl]-1-piperidylprop-2-en-1-one

1-(tert-Butyl)-2-bromo-4-nitrobenzene (6.885 g, 26.674 mmol, Step B),1-piperidylprop-2-en-1-one (4.827 g, 34.677 mmol, Step A), and TEA (7.44ml, 53.35 mmol) were dissolved into toluene (70 ml). To this solutionwas added Pd(OAc)₂ (60 mg, 0.267 mmol) and Pd(PPh₃)₄ (617 mg, 0.5335mmol). The mix was degassed with N₂ and heated in a sealed vessel at120° C. for 15 h. The reaction mixture was cooled to RT, filtered, andconcentrated in vacuo. The dark crude oil was eluted through a silicagel column with 15% to 22% EtOAc/hexanes gradient system to yield athick amber oil as the title intermediate.

Step D—Preparation of(2E)-3-[2-(tert-butyl)-5-aminophenyl]-1-piperidylprop-2-en-1-one

(2E)-3-[2-(tert-Butyl)-5-nitrophenyl]-1-piperidylprop-2-en-1-one (3.22g, 10.177 mmol, step C) was dissolved in dioxane (20 ml) and IpOH (40ml). To the N₂-degassed solution was added 10% by weight Pd/C catalyst(2 g). The mix was placed into a Parr hydrogenator and stirred for 18 hunder 60 psi H₂. The reaction was not complete the next day, so thereaction was continued for an additional 20 h with fresh catalyst. Themix was filtered through Celite® and concentrated in vacuo to give afoamy oil.

Step E—Preparation of 4-(tert-butyl)-3-(3-piperidylpropyl)phenylamine

(2E)-3-[2-(tert-Butyl)-5-aminophenyl]-1-piperidylprop-2-en-1-one (2.312g, 7.619 mmol, step D) was dissolved in THF (100 ml) at RT. To thissolution was added LiAlH₄ (434 mg, 11.43 mmol). After the reactionmixture stopped exotherming, it was heated at reflux at about 80° C. for4 h. The reaction was cooled to 0° C. and treated by dropwise additionof 0.458 ml H₂O, 0.730 ml 10% aqueous NaOH, and 1.19 ml H₂O,respectively. The mix was stirred at RT for 40 min. Na₂SO₄ (3 g) wasadded and the mix was stirred for 20 min. The mix was filtered throughCelite® and concentrated in vacuo. The crude was eluted through silicagel column with a gradient system of 95:5 to 90:10 CH₂Cl₂:MeOH, to yieldan amber thick oil as the title compound.

Step F—Preparation ofN-[4-(tert-butyl)-3-(3-piperidylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was prepared from4-(tert-butyl)-3-(3-piperidylpropyl)phenylamine (Step E) similar to themethod described in Example 82. MS: 486.2 (M+1). Calc'd. forC₃₀H₃₉N₅O—485.68.

Example 143

N-[4-(tert-Butyl)-3-(3-pyrrolidinylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS: 472.5 (M+1). Calc'd. for C₂₉H₃₇N₅O—471.65.

Example 144

N-[3-((1E)-4-Pyrrolidinylbut-1-enyl)-4-(tert-butyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS: 484.0 (M+1). Calc'd. for C₃₀H₃₇N₅O—483.66.

Example 145

N-[4-(tert-Butyl)-3-(3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS: 488.4 (M+1). Calc'd. for C₂₉H₃₇N₅O₂—487.65.

Example 146

N-[1-(2-Morpholin-4-ylethyl)indol-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of 1-(2-morpholin-4-ylethyl)indole-6-ylamine

K₂CO₃ (5.08 g, 36.726 mmol) was added to a slurry of 6-nitroindole(1.985 g, 12.242 mmol), 4-(2-chloroethyl)morpholine hydrochloride (2.278g, 12.242 mmol), and CH₃CN (100 ml). The mix was heated at reflux for 18h, then cooled to RT, filtered, and concentrated in vacuo. The crude waseluted through a silica gel column with a gradient of 3:97 to 5:95 andfinally 8:92 MeOH:CH₂Cl₂, to yield upon drying1-(2-morpholin-4-yl-ethyl)-6-nitro-1H-indole which was hydrogenated atregular condition described early to yield the title compound.

Step B—Preparation ofN-[1-(2-morpholin-4-ylethyl)indol-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was prepared from1-(2-morpholin-4-ylethyl)indole-6-ylamine (Step A) similar to the methoddescribed in Example 82. MS: 457.3 (M+1). Calc'd. for C₂₆H₂₈N₆O₂—456.55.

Example 147

N-[4-(tert-Butyl)phenyl]{2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of pyrimidine-4-yl formaldehyde

Pyrimidine-4-yl formaldehyde was prepared from 4-methylpyrimidinethrough a reference described in M. C. Liu et al., J Med. Chem., 1995,38 (21), 4234-4243.

Step B—Preparation ofN-[4-(tert-butyl)phenyl]{2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide

The title compound was prepared from pyrimidine-4-yl formaldehyde (StepA) similar to the method described in Example 82. MS (ES+): 362 (M+H);(ES−): 360 (M−H). Calc'd. for C₂₁H₂₃N₅O—361.19.

Example 148

N-(4-Chlorophenyl){2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide

MS (ES+): 340 (M+H); (ES−): 338 (M−H). Calc'd. for C₁₇H₁₄ClN₅O—339.09.

Example 149

{2-[(Pyrimidin-4-ylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide

MS (ES+): 374 (M+H); (ES−): 372 (M−H). Calc'd. for C₁₈H₁₄F₃N₅O—373.12.

Example 150

N-[4-(Isopropyl)phenyl]{4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamideStep A—Preparation of ethyl2-methylthio-4-[benzylamino]pyrimidine-5-carboxylate

A solution of ethyl 4-chloro-2-methylthio-pyrimidine-5-carboxylate (2.8g, 12.2 mmol) and 4-aminomethylpyridine (1.24 mL, 12.2 mmol) in EtOH (20mL) was heated at 70° C. for 2 h. The resulting suspension wasconcentrated, and the residue was purified by SiO₂ chromatography togive ethyl 2-methylthio-4-[benzylamino]pyrimidine-5-carboxylate. MS(ES+): 305 (M+H)⁺; (ES−): 303 (M−H)⁻. Calc'd C₁₅H₁₇N₃O₂S: 303.38.

Step B—Preparation ofN-[4-(isopropyl)phenyl]{2-methylthio-4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide

To a solution of ethyl2-methylthio-4-[benzylamino]-pyrimidine-5-carboxylate (0.1 g, 0.3 mmol,Step A) in EtOH (3 mL) was added 1 mL of aq. 1N NaOH solution. Theresulting mixture was stirred at 45° C. for 2 h. The resulting mixturewas neutralized with aq. 1N HCl and concentrated. To the residue in 3 mLof CH₂Cl₂ was added 4-isopropylaniline (90 mg, 0.66 mmol), HATU (0.18 g,0.45 mmol), and 0.5 mL of TEA (0.36 g, 3.5 mmol). The resulting mixturewas stirred at RT for 4 h and diluted with CH₂Cl₂. The organic solutionwas washed with H₂O, dried over Na₂SO₄ and concentrated. The residue waspurified by SiO₂ chromatography to giveN-[4-(isopropyl)phenyl]{2-methylthio-4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide.MS (ES+): 394 (M+H)⁺; (ES−): 392 (M−H)⁻. Calc'd C₂₁H₂₃N₅OS—393.51.

Step C—Preparation ofN-[4-(isopropyl)phenyl]{4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide

A mixture ofN-[4-(isopropyl)phenyl]{2-methylthio-4-[(4-pyridylmethyl)amino]pyrimidin-5-yl}carboxamide(50 mg, 0.13 mmol, Step B) and Raney-Ni in EtOH (10 mL) was heated atreflux for 2 h. The resulting mixture was filtered, and the filtrate wasconcentrated to give the titled compound. MS (ES+): 348 (M+H)⁺; (ES−):346 (M−H)⁻. Calc'd C₂₀H₂₁N₅O—347.42.

Example 151

(2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4-(tert-butyl)phenyl]carboxamideStep A—Preparation of2-{2-[2-(dimethylamino)ethoxy]ethoxy}pyridine-4-carbonitrile

To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexanewashed) and heated at 50° C. for 2 h. The warm sodium alkoxide solutionwas added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10mL). After the addition, the reaction mixture was heated to 70° C. for 2h, then DMF was removed in vacuo. The residue was partitioned betweenCH₂Cl₂/H₂O. The organic layer was washed with brine, dried over Na₂SO₄,and concentrated in vacuo to give a light yellow oil (5.6 g). MS: 236(M+1). Calc'd. for C₁₂H₁₇N₃O₂—235.29.

Step B—Preparation of(2-{2-[4-(aminomethyl)(2-pyridyloxy)]ethoxy}ethoxy)dimethylamine

2-{2-[2-(Dimethylamino)ethoxy]ethoxy}pyridine-4-carbonitrile (330 mg 1.4mmol, Step A) was dissolved in EtOH (10 mL) along with TEA (2 mL) andsuspended with Pd/C (10%, 40 mg). The reaction mixture was stirredovernight at RT under balloon filled with H₂. After removing theballoon, the reaction suspension was filtered through a layer ofCelite®. The Celite® layer was rinsed with MeOH. The combined filtratewas concentrated in vacuo to give a light yellow oil. MS: 240 (M+1).Calc'd. for C₁₂H₂₁N₃O₂—239.32.

Step C—Synthesis of 2-fluoropyridine-3-carboxylic acid

To a solution of 2-fluoropyridine (10 g, 100 mmol) in THF (150 mL) under−78° C. was dropwise added an LDA solution (2M inheptane/THF/ethylbenzene, 60 mL). The mixture was stirred at −78° C. for3 h after the addition of LDA then quenched with N₂ dried solid CO₂.After warming to RT, the reaction was partitioned between EtOAc (100 mL)and H₂O (200 mL). The aqueous layer was acidified to pH between 3-4 andextracted with EtOAc. The organic solution was collected and washed withbrine and dried over Na₂SO₄. After removing solvent in vacuum, a brownoil was received as the desired compound. MS: 140 (M−H). Calc'd. forC₆H₄FNO₂—141.10.

Step D—Synthesis of 2-fluoropyridine-3-carbonyl chloride

2-Fluoropyridine-3-carboxylic acid (7 g, Step C) was suspended in SOCl₂(100 mL). After heating under reflux for 2 h, the mixture becamehomogeneous. Excess SOCl₂ was removed in vacuo to afford a brown solidas desired product.

Step E—Synthesis ofN-[4-(tert-butyl)phenyl]2-fluoropyridine-3-carboxamide

To a suspension of 2-fluoropyridine-3-carbonyl chloride (3.2 g, 20 mmol,Step D) and NaHCO₃ (4 g, 48 mmol) in CH₂Cl₂ added in dropwise a solutionof 4-tert butylaniline (3.0 g, 20 mmol). After the addition, thesuspension was stirred at RT for 5 h. Solid inorganic salts were removedvia filtration. The filtrate was concentrated to afford a brown solid asdesired compound. MS: 273 (M+H). Calc'd. for C₁₆H₁₂FN₂O—272.33.

Step F—Synthesis of{2-[({2-[2-(2-N,N-dimethylaminoethoxy)ethoxy]-4-pyridyl}methyl)amino](3-pyridyl)}-N-(4-tert-butylphenyl)carboxamide

N-[4-(tert-Butyl)phenyl]2-fluoropyridine-3-carboxamide (544 mg, 2 mmol,Step E) was dissolved in pyridine (5 mL) along with(2-{2-[4-(aminomethyl) (2-pyridyloxy)]ethoxy}ethoxy)dimethylamine (570mg, 2.38 mmol, Step A). The reaction was heated to 85° C. for 48 h.After removal of pyridine in vacuo, the residue was dissolved in CH₂Cl₂and washed with NaHCO₃ (Sat. aq), then brine. After drying over Na₂SO₄,the CH₂Cl₂ solution was concentrated in vacuo and purified via prep.HPLC(H₂O/CH₃CN: 5%-95% gradient) to give the title product. MS: 492(M+1). Calc'd. for C₂₈H₃₇N₅O₃—491.63

The following compounds (Examples 152-157) were analogously synthesizedby the method described in Example 151 unless specifically described.Detailed intermediate preparations are included.

Example 152

{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-(2-piperidylethoxy)-1-(trifluoromethyl)ethyl]phenyl}carboxamideStep A—Preparation of4-[2,2,2-trifluoro-1-(2-piperidin-1-yl-ethoxy)-1-trifluoromethyl-ethyl]-phenylamine

DEAD (366 mg, 2.1 mmol) was added drop-wise to the solution of2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (520 mg, 2 mmol),2-piperidylethan-1-ol (260 mg, 2 mmol) and PPh₃ (550 mg, 2.1 mmol) inTHF (10 mL). The mixture was stirred for 2 h. The reaction waspartitioned between EtOAc and aqueous NaHCO₃ solution and the organicphase was washed with brine. After concentrated in vacuo, the organicresidue was purified by flash chromatography on silica to give the titleintermediate.

Step B—Preparation of{2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-1-(2-piperidylethoxy)-1-(trifluoromethyl)ethyl]phenyl}carboxamide

The title compound was synthesized by the method described in Example151. MS: 582 (M+1). Calc'd. for C₂₈H₂₉F₆N₅O₂—581.56.

Example 153

(2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}(4-pyridyl))methyl]amino}-6-fluoro(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamideStep A Preparation of 2,6-difluoropyridine-3-carbonyl chloride

The title compound was prepared similar to that described in Example151, Step D.

Step B—Preparation of(2-{[(2-{2-[2-(dimethylamino)-ethoxy]ethoxy}(4-pyridyl))methyl]amino}-6-fluoro(3-pyridyl))-N-[3-(trifluoromethyl)phenyl]carboxamide

The title compound was synthesized by the method described in Example151. MS: 522 (M+1). Calc'd. for C₂₅H₂₇F₄N₅O₃—521.51.

Example 154

N-[4-(tert-Butyl)phenyl]{6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of N-(4-tert-butyl-phenyl)-2,6-difluoro-nicotinamide

A solution of 2,6-difluoropyridine-3-carboxylic acid (3.2 g, 20 mmol),t-butylaniline (3.0 g, 20 mmol), HOBt (2.6 g, 20 mmol), EDAC (8 g, 40mmol), and DIEA (8 mL) in CH₂Cl₂ (80 mL) was stirred at RT for 1 h. Themixture was washed with aq. NaHCO₃ and brine. The organic solution wasdried over Na₂SO₄ and concentrated in vacuo. The residue was purifiedvia flash chromatography on silica (Hex:EtOAc=4:1) to give a lightyellow flaky crystal as desired product.

Step B—Preparation ofN-[4-(tert-butyl)phenyl]{6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was synthesized similar to that described in Example151 except that it was synthesized at RT. MS: 379 (M+1). Calc'd. forC₂₂H₂₃FN₄O—378.45.

The following compounds were analogously synthesized by the methoddescribed in Example 154. Detailed intermediate preparations aredescribed.

Example 155

{6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[4-(isopropyl)phenyl]carboxamide

MS: 365 (M+1). Calc'd. for C₂₁H₂₁FN₄O—364.42.

Example 156

{6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide

MS: 391 (M+1). Calc'd. for C₁₉H₁₄F₄N₄O—390.34.

Example 157

N-(1-Bromo(3-isoquinolyl)){6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-carboxamide

MS: 452/454 (M+1). Calc'd. for C₂₁H₁₅BrFN₅O—452.29.

Example 158

N-(4-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of(2-chloro(3-pyridyl))-N-(4-phenoxy-phenyl)carboxamide

2-Chloronicotinic acid (0.78 g, 5.0 mmol) and TEA (1.6 ml, 10.0 mmol)were added to anhydrous THF (50 ml) under a N₂ atmosphere at 0° C. Afterstirring for 5 min, ethyl chloroformate (0.54 g, 5.0 mmol) was addeddropwise and the mixture gradually came to RT over a period of 1 h.4-Phenoxyaniline (0.83 g, 5.0 mmol) was added and the mixture wasstirred for 14 h. The mixture was partitioned between H₂O and EtOAc. Theaqueous layer was extracted two additional times with EtOAc (50 ml). Thecombined organic layers were then washed with brine, dried over Na₂SO₄,and evaporated. The resulting brown oil was used directly in thesubsequent reaction without further purification. MS m/z: 325 (M+1).Calc'd for C₁₈H₁₃ClN₂O₂: 324.07.

Step B—Preparation ofN-(4-phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride

The amide (0.500 g, 1.5 mmol, Step A) and 4-aminomethylpyridine (0.486g, 4.5 mmol) were combined and heated neat at 90° C. for 48 h. Aftercooling to RT, the mixture was poured into a saturated NaHCO₃ solutionand extracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, and evaporated. The resulting brown oil waspurified by column chromatography with EtOAc/hexanes (2:1) as eluant toleaveN-(4-phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}formamide as aclear oil. This material was converted directly into the HCl salt bydissolution in MeOH (5 ml), treatment with 3 equivalents of an HClethereal solution, and evaporation of solvent to leave the titledproduct as a light yellow solid. MS (ES+): 397 (M+H)⁺; (ES−): 395 (M−H).Calc'd. for C₂₄H₂₀N₄O₂—396.16.

The following compounds (Examples 159-161) were prepared similar to themethod described in Example 158.

Example 159

N-(4-Biphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS: 381 (M+1); 379 (M−1). Calc'd. for C₂₄H₂₀N₄O—380.16.

Example 160

N-(3-Phenoxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride

MS: 397 (M+1); 395 (M−1). Calc'd. for C₂₄H₂₀N₄O₂—396.16.

Example 161

N-(4-Cyclohexylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

MS: 387 (M+1); 385 (M−1). Calc'd. for C₂₄H₂₆N₄O—386.21.

Example 162

N-(4-Imidazol-1-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamideStep A—Preparation of(2-Chloro(3-pyridyl))-N-(4-imidazolylphenyl)carboxamide

A slurry of 4-imidazolylphenylamine (15.9 mg, 0.100 mmol),polymer-supported DIPEA (0.100 g, 0.362 mmol, 3.62 mmol/g loading) inCH₂Cl₂ (2 ml) was treated with a 2-chloropyridine-3-carbonyl chloridesolution (0.10 M, 0.200 mmol, 2.0 ml, 2.0 eq) in CH₂Cl₂. The mixture wasvortexed at RT for 14 h. Afterwards, the excess acid chloride wasremoved by treating the reaction mixture with polymer-supportedtrisamine resin (0.100 g, 0.375 mmol, 3.75 mmol/g loading). The slurrywas shaken at RT for an additional 18 h. The reaction mixture wasfiltered, rinsed with CH₂Cl₂ (1 ml), and the filtrate was concentratedunder reduced pressure. The resulting brown oil was used directly in thesubsequent reaction.

Step B—Synthesis ofN-(4-imidazolylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamidehydrochloride

(2-Chloro-(3-pyridyl))-N-(4-imidazolylphenyl)-carboxamide was treatedwith 4-aminomethylpyridine (0.100 g, 0.93 mmol) and heated neat at 120°C. for 18 h. After cooling to RT, the material was purified bypreparative HPLC. The final product was converted into an HCl salt bydissolution in a minimum of MeOH, treatment with an HCl etherealsolution, and evaporation of solvent. MS: (ES+) 371 (M+1)⁺; (ES−): 369(M−1)⁻. Calc'd. for C₂₁H₁₈N₆O—370.15.

The following compounds (Examples 163-166) were analogously synthesizedby the method described in Example 162.

Example 163

N-(4-Morpholin-4-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was isolated as the HCl salt. MS: 390 (M+1); 388(M−1). Calc'd. for C₂₂H₂₃N₅O₂—389.19.

Example 164

N-(4-Cyanonaphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide

The title compound was isolated as the HCl salt. MS: 380 (M+1); 378(M−1). Calc'd. for C₂₃H₁₇N₅O—379.14.

Example 165

{2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyl]carboxamide

The title compound was isolated as the HCl salt. MS: 373 (M+1); 371(M−1). Calc'd. for C₁₉H₁₅F₃N₄O—372.12.

Example 166

Methyl-({2-[(4-pyridylmethyl)amino]-3-pyridyl}carbonylamino)benzoate

The title compound was isolated as the HCl salt. MS: 363 (M+1); 361(M−1). Calc'd. for C₂₀H₁₈N₄O₃—362.14.

The following compounds were synthesized by a procedure similar to themethod described in Example 3, using an aldehyde to react with theaminopyridine core via reductive amination.

Example 167

N-[4-(Isopropyl)phenyl]{2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide

MS: (ES+) 397 (M+H); (ES−) 395 (M−H). Calc'd. for C₂₅H₂₄N₄O—396.20.

Example 168

N-[4-(tert-Butyl)phenyl]{2-[(6-quinolylmethyl)amino](3-pyridyl)}carboxamide

MS (ES+): 411 (M+H); (ES−): 409 (M−H)⁻. Calc'd. for C₂₆H₂₆N₄O—410.51.

Example 169

{2-[(6-Quinolylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide

MS (ES+): 423 (M+H); (ES−): 421 (M−H). Calc'd. for C₂₃H₁₇F₃N₄O: 422.14.

Other compounds included in this invention are set forth in Tables 3-9below.

TABLE 3

# R¹ R² n 170. 2-chlorophenyl H 1 171. 4-benzimidazolyl H 1 172.5-benzimidazolyl H 1 173. 7-benzimidazolyl H 1 174. 2-chlorophenyl 5-Br1 175. 3-isoquinolinyl 5-Br 1 176. 2-quinolinyl 5-Br 1 177.2-benzthiazolyl 5-Br 1 178. 2-benzimidazolyl 5-Br 1 179.4-benzimidazolyl 5-Br 1 180. 5-benzimidazolyl 5-Br 1 181.6-benzimidazolyl 5-Br 1 182. 7-benzimidazolyl 5-Br 1 183. 4-chlorophenylH 3 184. 4-chlorophenyl 3-pyridyl 1 185. 4-pyridyl H 1 186. 4-pyridyl6-CH₃ 1 187. 4-chlorophenyl- 5-Cl 1 188. 3,4-dichlorophenyl- 5-Br 1 189.4-fluorophenyl 6-CH₃ 1 190. 3-chlorophenyl 6-CH₃ 1 191. 3-fluorophenyl6-CH₃ 1 192. 3-fluoro-4-methoxyphenyl 6-CH₃ 1 193.3-fluoro-4-methylphenyl 6-Cl 1 194. 4-phenoxyphenyl H 1 195.3-phenoxyphenyl H 1 196. 4-biphenyl H 1 197. 4-cyclohexylphenyl H 1 198.2-quinolyl H 1 199. 3-isoquinolyl H 1 200. 3-quinolyl H 1 201.1-isoquinolyl H 1 202. 5-quinolyl H 1 203. 5-isoquinolyl H 1 204.6-quinolyl H 1 205. 6-isoquinolyl H 1 206. 7-quinolyl H 1 207.7-isoquinolyl H 1 208. 4-quinolyl H 1 209. 4-isoquinolyl H 1 210.4-pyridyl H 1 211. 4-pyrimidinyl H 1 212. 2-pyrimidinyl H 1 213.6-pyrimidinyl H 1 214. 4-pyridazinyl H 1 215. 5-pyridazinyl H 1 216.4-indolyl H 1 217. 5-isoindolyl H 1 218. 5-naphthyridinyl H 1 219.6-quinozalinyl H 1 220. 6-isoquinolyl H 1 221. 4-naphthyridinyl H 1 222.5-quinozalinyl H 1 223. 4-naphthyridinyl H 1 224. 7-tetrahydroquinolinylH 1 225. 6-indazolyl H 1 226. 6-isoindolyl H 1 227. 5-indazolyl H 1 228.5-isoindolyl H 1 229. 6-benzothienyl H 1 230. 6-benzofuryl H 1 231.5-benzothienyl H 1 232. 5-benzofuryl H 1 233. 2-benzimidazolyl H 1 234.2-benzoxazolyl H 1 235. 2-benzthiazolyl H 1 236. 6-benzimidazolyl H 1237. 6-benzoxazolyl H 1 238. 6-benzthiazolyl H 1 239. 2-quinazolinyl H 1240. 3-(phenoxy)-6-pyridyl H 1 241. 4-(phenylcarbonyl)phenyl H 1 242.4-(phenylamino)phenyl H 1 243. 4-cyclohexyloxyphenyl H 1 244.4-(3-thienyl)phenyl H 1 245. 4-(pyrazol-3-yl)phenyl H 1 246.4-chlorophenyl 6-F 2 247. 4-pyridyl 6-Cl 1 248. 3-methoxyphenyl 6-F 1249. 4-hydroxyphenyl 6-Cl 1 250. 3-hydroxyphenyl H 1 251.2-hydroxyphenyl H 1 252. 4-chlorophenyl 6-F 1 253. 4-phenoxyphenyl 6-F 1254. 4-biphenyl 6-phenyl 1 255. 4-hydroxyphenyl 6-phenyl 1 256.4-cyclohexylphenyl 6-F 1 257. 3-isoquinolyl 6-phenyl 1 258.4-piperidinylmethylphenyl H 1 259. 4-morpholinylmethylphenyl H 1

Table 4a.

# R¹ 260. 4-chlorophenyl 261. 3,4-dichlorophenyl 262. 4-phenoxyphenyl263. 4-biphenyl 264. 4-cyclohexylphenyl 265. 3-isoquinolyl Table 4b.

# R¹ 266. 4-chlorophenyl 267. 3,4-dichlorophenyl 268. 4-phenoxyphenyl269. 4-biphenyl 270. 4-cyclohexylphenyl 271. 3-isoquinolyl Table 4c.

# R¹ A⁵ 272. 4-chlorophenyl NH 273. 3,4-dichlorophenyl NH 274.4-phenoxyphenyl NH 275. 4-biphenyl NH 276. 4-cyclohexylphenyl NH 277.3-isoquinolyl NH 278. 4-chlorophenyl O 279. 3,4-dichlorophenyl O 280.4-phenoxyphenyl O 281. 4-biphenyl O 282. 4-cyclohexylphenyl O 283.3-isoquinolyl O 284. 3,4-dichlorophenyl S 285. 4-phenoxyphenyl S 286.4-biphenyl S 287. 4-cyclohexylphenyl S 288. 3-isoquinolyl S Table 4d.

# R¹ A⁵ 289. 4-chlorophenyl NH 290. 3,4-dichlorophenyl NH 291.4-phenoxyphenyl NH 292. 4-biphenyl NH 293. 4-cyclohexylphenyl NH 294.3-isoquinolyl NH 295. 4-chlorophenyl O 296. 3,4-dichlorophenyl O 297.4-phenoxyphenyl O 298. 4-biphenyl O 299. 4-cyclohexylphenyl O 300.3-isoquinolyl O 301. 3,4-dichlorophenyl S 302. 4-phenoxyphenyl S 303.4-biphenyl S 304. 4- cyclohexylphenyl S 305. 3-isoquinolyl S Table 4e.

# R¹ A⁵ 306. 4-chlorophenyl NH 307. 3,4-dichlorophenyl NH 308.4-phenoxyphenyl NH 309. 4-biphenyl NH 310. 4-cyclohexylphenyl NH 311.3-isoquinolyl NH 312. 4-chlorophenyl O 313. 3,4-dichlorophenyl O 314.4-phenoxyphenyl O 315. 4-biphenyl O 316. 4-cyclohexylphenyl O 317.3-isoquinolyl O 318. 3,4-dichlorophenyl S 319. 4-phenoxyphenyl S 320.4-biphenyl S 321. 4-cyclohexylphenyl S 322. 3-isoquinolyl S Table 4f.

# R¹ A⁵ 323. 4-chlorophenyl NH 324. 3,4-dichlorophenyl NH 325.4-phenoxyphenyl NH 326. 4-biphenyl NH 327. 4-cyclohexylphenyl NH 328.3-isoquinolyl NH 329. 4-chlorophenyl O 330. 3,4-dichlorophenyl O 331.4-phenoxyphenyl O 332. 4-biphenyl O 333. 4-cyclohexylphenyl O 334.3-isoquinolyl O 335. 3,4-dichlorophenyl S 336. 4-phenoxyphenyl S 337.4-biphenyl S 338. 4-cyclohexylphenyl S 339. 3-isoquinolyl S Table 4g.

# R¹ A⁵ 340. 4-chlorophenyl NH 341. 3,4-dichlorophenyl NH 342.4-phenoxyphenyl NH 343. 4-biphenyl NH 344. 4-cyclohexylphenyl NH 345.3-isoquinolyl NH 346. 4-chlorophenyl O 347. 3,4-dichlorophenyl O 348.4-phenoxyphenyl O 349. 4-biphenyl O 350. 4-cyclohexylphenyl O 351.3-isoquinolyl O Table 4h.

# R¹ A⁵ 352. 4-chlorophenyl NCH₃ 353. 3,4-dichlorophenyl NCH₃ 354.4-phenoxyphenyl NCH₃ 355. 4-biphenyl NH 356. 4-cyclohexylphenyl NH 357.4-tert-butylphenyl NCH₃ 358. 4-chlorophenyl O 359. 3,4-dichlorophenyl O360. 4-phenoxyphenyl O 361. 4-biphenyl O 362. 4-cyclohexylphenyl O 363.3-isoquinolyl O

TABLE 5

# R Y R¹ R² 364. 4-pyridyl —NHSO₂— 4-chlorophenyl H 365. 4-pyridyl—NHSO₂— 4-chlorophenyl 5-Br 366. 4-pyridyl —NHSO₂— 3-chlorophenyl H 367.4-pyridyl —NHSO₂— 3-chlorophenyl 5-Br 368. 4-pyridyl —NHSO₂—4-phenoxyphenyl H 369. 4-pyridyl —NHSO₂— 4-biphenyl H 370. 4-pyridyl—NHSO₂— 3-isoquinolyl H 371. 4-pyridyl —NHSO₂— 3-isoquinolyl 5-Br 372.5-quinolyl —NHSO₂— 4-chlorophenyl H 373. 5-quinolyl —NHSO₂—4-chlorophenyl 5-Br 374. 5-quinolyl —NHSO₂— 3-chlorophenyl H 375.5-quinolyl —NHSO₂— 3-chlorophenyl 5-Br 376. 5-quinolyl —NHSO₂—4-phenoxyphenyl H 377. 6-quinolyl —NHSO₂— 4-biphenyl H 378. 5-quinolyl—NHSO₂— 3-isoquinolyl H 379. 6-quinolyl —NHSO₂— 3-isoquinolyl 5-Br 380.4-pyridyl —NHCH₂—

H 381.

—NHCH₂—

H 382.

—NHCH₂—

H 383.

—NHCH₂—

H 384.

—NHCH₂—

H 385.

—NHCH₂— 4-CF₃-phenyl H 386.

—NHCH₂—

H 387.

—NHCH₂—

H 388.

—NHCH₂—

H 389.

—NHCH₂— 3-CF₃-phenyl H 390.

—NHCH₂—

H 391.

—NHCH₂—

H 392.

—NHCH₂— 4-CF₃-phenyl H 393.

—NHCH₂—

H 394.

—NHCH₂—

H 395.

—NHCH₂—

H 396.

—NHCH₂— 3-CF₃-phenyl H 397.

—NHCH₂—

H 398.

—NHCH₂—

H 399.

—NHCH₂—

H 400.

—NHCH₂— 4-CF₃-phenyl H 401.

—NHCH₂—

H 402.

—NHCH₂—

H 403.

—NHCH₂— 3-CF₃-phenyl H 404.

—NHCH₂—

H 405.

—NHCH₂—

H 406.

—NHCH₂— 4-CF₃-phenyl H 407.

—NHCH₂—

H 408.

—NHCH₂—

H 409.

—NHCH₂—

H 410.

—NHCH₂— 3-CF₃-phenyl H 411.

—NHCH₂—

H 412.

—NHCH₂—

H 413.

—NHCH₂— 4-CF₃-phenyl H 414. 4-pyridyl —NHCH₂—

H 415. 4-pyridyl —NHCH₂—

H 416. 4-pyridyl —NHCH₂—

H 417. 4-pyridyl —NHCH₂—

H 418. 4-pyridyl —NHCH₂—

H 419. 4-pyrimidinyl —NHCH₂—

H 420. 4-pyrimidinyl —NHCH₂—

H 421. 4-pyrimidinyl —NHCH₂—

H 422. 4-pyrimidinyl —NHCH₂—

H 423. 4-pyrimidinyl —NHCH₂—

H 424. 4-pyrimidinyl —NHCH₂—

H 425. 4-pyrimidinyl —NHCH₂—

H 426. 4-pyrimidinyl —NHCH₂—

H 427. 4-pyrimidinyl —NHCH₂—

H 428. 4-pyrimidinyl —NHCH₂—

H 429. 3-pyridyl —NH(CH₂)₂—

H 430. 3-pyridyl —NH(CH₂)₂—

H 431. 3-pyridyl —NH(CH₂)₂—

H 432. 3-pyridyl —NH(CH₂)₂—

H 433. 3-pyridyl —NH(CH₂)₂—

H 434. 3-pyridyl —NH(CH₂)₂—

H 435. 3-pyridyl —NH(CH₂)₂—

H 436. 3-pyridyl —NH(CH₂)₂—

H 437. 3-pyridyl —NH(CH₂)₂—

H 438.

—NHCH₂—

H 439.

—NHCH₂—

H 440.

—NHCH₂—

H 441.

—NHCH₂—

H 442.

—NHCH₂—

H 443.

—NHCH₂—

H 444.

—NHCH₂—

H 445.

—NHCH₂—

H 446.

—NHCH₂—

H 447.

—NHCH₂—

H 448.

—NHCH₂—

449.

—NHCH₂—

H 450.

—NHCH₂—

H 451.

—NHCH₂—

H 452.

—NHCH₂—

H 453.

—NHCH₂—

H 454.

—NHCH₂—

H 455.

—NHCH₂—

H 456.

—NHCH₂—

H 457.

—NHCH₂—

H 458.

—NHCH₂—

H 459.

—NHCH₂—

H 460.

—NHCH₂—

H 461.

—NHCH₂—

H 462. 4-pyridyl —NHCH₂—

H 463. 4-pyridyl —NHCH₂—

H 464. 4-pyridyl —NHCH₂—

H 465. 4-pyridyl —NHCH₂—

H 466. 4-pyridyl —NHCH₂—

H 467. 4-pyridyl —NHCH₂—

H 468. 4-pyridyl —NHCH₂—

H 469. 4-pyridyl —NHCH₂—

H 470. 3-pyridyl —NH(CH₂)₂—

H 471. 3-pyridyl —NH(CH₂)₂—

H 472. 3-pyridyl —NH(CH₂)₂—

H 473. 3-pyridyl —NH(CH₂)₂—

H 474. 3-pyridyl —NH(CH₂)₂—

H 475. 3-pyridyl —NH(CH₂)₂—

H 476. 3-pyridyl —NH(CH₂)₂—

H 477. 3-pyridyl —NH(CH₂)₂—

H 478. 3-pyridyl —NH(CH₂)₂—

H 479. 4-pyrimidinyl —NHCH₂—

H 480. 4-pyrimidinyl —NHCH₂—

H 481. 4-pyrimidinyl —NHCH₂—

H 482. 4-pyrimidinyl —NHCH₂—

H 483. 4-pyrimidinyl —NHCH₂—

H 484. 4-pyrimidinyl —NHCH₂—

H 485. 4-pyrimidinyl —NHCH₂—

H 486. 4-pyrimidinyl —NHCH₂—

H 487. 4-pyrimidinyl —NHCH₂—

H 488. 4-pyrimidinyl —NHCH₂—

H 489. 4-pyrimidinyl —NHCH₂—

H 490. 4-pyrimidinyl —NHCH₂—

H 491.

—NHCH₂—

H 492.

—NHCH₂—

H 493.

—NHCH₂—

H 494.

—NHCH₂—

H 495.

—NHCH₂—

H 496.

—NHCH₂—

H 497.

—NHCH₂—

H 498.

—NHCH₂—

H 499.

—NHCH₂—

H 500.

—NHCH₂—

H 501.

—NHCH₂—

H 502.

—NHCH₂—

H 503.

—NHCH₂—

H 504.

—NHCH₂—

H 505.

—NHCH₂—

H 506.

—NHCH₂—

H 507.

—NHCH₂—

H 508.

—NHCH₂—

H 509.

—NHCH₂—

H 510.

—NHCH₂—

H 511.

—NHCH₂—

H 512.

—NHCH₂—

H 513.

—NHCH₂—

H 514.

—NHCH₂—

H 515.

—NHCH₂—

H 516.

—NHCH₂—

H 517.

—NHCH₂—

H 518.

—NHCH₂—

H 519.

—NHCH₂—

H 520.

—NHCH₂—

H 521.

—NHCH₂—

H 522.

—NHCH₂—

H 523.

—NHCH₂—

H 524.

—NHCH₂—

H 525. 4-pyridyl —NHCH₂— 3-CF₃-phenyl H 526. 4-pyridyl —NHCH₂—

H 527. 4-pyridyl —NHCH₂—

H 528. 4-pyridyl —NHCH₂—

H 529. 4-pyridyl —NHCH₂—

H 530. 4-pyridyl —NHCH₂—

H 531. 4-pyridyl —NHCH₂—

H 532. 4-pyridyl —NHCH₂—

H 533. 4-pyridyl —NHCH₂—

H 534. 3-pyridyl —NH(CH₂)₂—

H 535. 3-pyridyl —NH(CH₂)₂—

H 536. 3-pyridyl —NH(CH₂)₂—

H 537. 3-pyridyl —NH(CH₂)₂—

H 538. 3-pyridyl —NH(CH₂)₂—

H 539. 4-pyridyl —NHCH₂—

H 540. 4-pyrimidinyl —NHCH₂—

H 541. 4-pyrimidinyl —NHCH₂—

H 542. 4-pyrimidinyl —NHCH₂—

H 543. 4-pyrimidinyl —NHCH₂—

H 544. 4-pyrimidinyl —NHCH₂—

H 545. 4-pyrimidinyl —NHCH₂—

H 546. 4-pyrimidinyl —NHCH₂—

H 547. 4-pyrimidinyl —NHCH₂—

H 548. 4-pyrimidinyl —NHCH₂—

H 549. 4-pyrimidinyl —NHCH₂—

H 550.

—NHCH₂— 3-CF₃-phenyl H 551.

—NHCH₂—

H 552.

—NHCH₂—

H 553.

—NHCH₂—

H 554.

—NHCH₂—

H 555.

—NHCH₂—

H 556.

—NHCH₂—

H 557.

—NHCH₂— 3-CF₃-phenyl H 558.

—NHCH₂—

H 559.

—NHCH₂—

H 560.

—NHCH₂—

H 561.

—NHCH₂—

H 562.

—NHCH₂—

H 563.

—NHCH₂—

H 564.

—NHCH₂— 3-CF₃-phenyl H 565.

—NHCH₂—

H 566.

—NHCH₂—

H 567.

—NHCH₂—

H 568.

—NHCH₂—

H 569.

—NHCH₂—

H 570.

—NHCH₂—

H 571.

—NHCH₂—

H 572.

—NHCH₂—

H 573.

—NHCH₂—

H 574.

—NHCH₂— 3-CF₃-phenyl H 575.

—NHCH₂—

H 576.

—NHCH₂—

H 577.

—NHCH₂—

H 578.

—NHCH₂—

H 579.

—NHCH₂—

H 580.

—NHCH₂—

H 581. 4-pyrimidinyl —NHCH₂—

H 582. 4-pyrimidinyl —NHCH₂—

H 583. 4-pyrimidinyl —NHCH₂—

H 584.

—NHCH₂—

H 585.

—NHCH₂—

H 586.

—NHCH₂—

H 587.

—NHCH₂—

H 588.

—NHCH₂—

H 589.

—NHCH₂—

H 590.

—NHCH₂—

H 591.

—NHCH₂—

H 592.

—NHCH₂—

H 593.

—NHCH₂—

H 594.

—NHCH₂—

H 595.

—NHCH₂—

H 596.

—NHCH₂—

H 597.

—NHCH₂—

H 598.

—NHCH₂—

H 599.

—NHCH₂—

H 600.

—NHCH₂—

H 601.

—NHCH₂—

H 602.

—NHCH₂— 3-CF₃-phenyl H 603.

—NHCH₂— 4-CF₃-phenyl H 604.

—NHCH₂—

H 605.

—NHCH₂—

H 606.

—NHCH₂—

H 607.

—NHCH₂— 3-CF₃-phenyl H 608.

—NHCH₂—

H 609.

—NHCH₂— 4-CF₃-phenyl H 610.

—NHCH₂—

H 611.

—NHCH₂—

H 612.

—NHCH₂— 3-CF₃-phenyl H 613.

—NHCH₂— 4-CF₃-phenyl H 614.

—NHCH₂—

H 615.

—NHCH₂—

H 616.

—NHCH₂—

H 617.

—NHCH₂—

H 618.

—NHCH₂— 3-CF₃-phenyl H 619.

—NHCH₂— 4-CF₃-phenyl H 620.

—NHCH₂—

H 621.

—NHCH₂—

H 622.

—NHCH₂—

H 623.

—NHCH₂— 3-CF₃-phenyl H 624.

—NHCH₂— 4-CF₃-phenyl H 625. 4-pyridyl —NHCH₂—

H 626.

—NHCH₂—

H 627.

—NHCH₂—

H 628.

—NHCH₂—

H 629.

—NHCH₂—

H 630.

—NHCH₂—

H 631.

—NHCH₂—

H 632.

—NHCH₂—

H 633. 3-pyridyl —NH(CH₂)₂—

H 634. 4-pyrimidinyl —NHCH₂—

H 635. 4-pyridyl —NHCH₂—

H

TABLE 6

# R¹ n R² 636. 4-chlorophenyl 1 6-F 637. 3,4-dichlorophenyl 1 H 638.4-fluorophenyl 1 H 639. 3-chlorophenyl 1 H 640. 3-fluorophenyl 1 H 641.3-fluoro-4-methoxyphenyl 1 H 642. 3-fluoro-4-methylphenyl 2 H 643.4-phenoxyphenyl 1 H 644. 3-phenoxyphenyl 1 H 645. 4-biphenyl 1 H 646.4-cyclohexylphenyl 1 H 647. 2-quinolyl 1 H 648. 3-isoquinolyl 1 H 649.3-quinolyl 1 H 650. 1-isoquinolyl 1 H 651. 5-quinolyl 1 H 652.5-isoquinolyl 1 H 653. 6-quinolyl 1 H 654. 6-isoquinolyl 1 H 655.7-quinolyl 1 H 656. 7-isoquinolyl 1 H 657. 4-quinolyl 1 H 658.4-isoquinolyl 1 H 659. 4-pyridyl 1 6-F 660. 4-pyrimidinyl 1 H 661.2-pyrimidinyl 1 H 662. 6-pyrimidinyl 1 H 663. 4-pyridazinyl 1 H 664.5-pyridazinyl 1 H 665. 4-indolyl 1 H 666. 5-isoindolyl 1 H 667.5-naphthyridinyl 1 H 668. 6-quinozalinyl 1 H 669. 6-isoquinolyl 1 H 670.4-naphthyridinyl 1 H 671. 5-quinozalinyl 1 H 672. 4-naphthyridinyl 1 H673. tetrahydroquinolinyl 1 H 674. 6-indazolyl 1 H 675. 6-isoindolyl 1 H676. 5-indazolyl 1 H 677. 5-isoindolyl 1 H 678. 6-benzothienyl 1 H 679.6-benzofuryl 1 H 680. 5-benzothienyl 1 H 681. 5-benzofuryl 1 H 682.2-benzimidazolyl 1 H 683. 2-benzoxazolyl 1 H 684. 2-benzthiazolyl 1 H685. 6-benzimidazolyl 1 H 686. 6-benzoxazolyl 1 H 687. 6-benzthiazolyl 1H 688. 2-quinazolinyl 1 H 689. 3-(phenoxy)-6-pyridyl 1 H 690.4-(phenylcarbonyl)phenyl 1 H 691. 4-(phenylamino)phenyl 1 H 692.cyclohexyloxyphenyl 1 H 693. 4-(3-thienyl)phenyl 1 H 694.4-(pyrazol-3-yl)phenyl 1 6-CH₃

TABLE 7

# R¹ n R² 695. 4-chlorophenyl 1 6-Cl 696. 3,4-dichlorophenyl 1 5-Cl 697.4-fluorophenyl 1 H 698. 3-chlorophenyl 1 H 699. 3-fluorophenyl 1 H 700.3-fluoro-4-methoxyphenyl 1 H 701. 3-fluoro-4-methylphenyl 1 H 702.4-phenoxyphenyl 1 H 703. 3-phenoxyphenyl 1 H 704. 4-biphenyl 1 H 705.4-cyclohexylphenyl 1 H 706. 2-quinolyl 1 H 707. 3-isoquinolyl 1 H 708.3-quinolyl 1 H 709. 1-isoquinolyl 1 H 710. 5-quinolyl 1 H 711.5-isoquinolyl 1 H 712. 6-quinolyl 1 H 713. 6-isoquinolyl 1 H 714.7-quinolyl 1 H 715. 7-isoquinolyl 1 H 716. 4-quinolyl 1 H 717.4-isoquinolyl 1 H 718. 4-pyridyl 1 H 719. 4-pyrimidinyl 1 H 720.2-pyrimidinyl 1 H 721. 6-pyrimidinyl 1 H 722. 4-pyridazinyl 1 H 723.5-pyridazinyl 1 H 724. 4-indolyl 1 H 725. 5-isoindolyl 1 H 726.5-naphthyridinyl 1 H 727. 6-quinozalinyl 1 H 728. 6-isoquinolyl 1 H 729.4-naphthyridinyl 1 H 730. 5-quinozalinyl 1 H 731. 4-naphthyridinyl 1 H732. tetrahydroquinolinyl 1 H 733. 6-indazolyl 1 H 734. 6-isoindolyl 1 H735. 5-indazolyl 1 H 736. 5-isoindolyl 1 H 737. 6-benzothienyl 1 H 738.6-benzofuryl 1 H 739. 5-benzothienyl 1 H 740. 5-benzofuryl 1 H

TABLE 8

# R¹ n R² 741. 2-benzimidazolyl 1 H 742. 2-benzoxazolyl 1 H 743.2-benzthiazolyl 1 H 744. 6-benzimidazolyl 1 H 745. 6-benzoxazolyl 1 H746. 6-benzthiazolyl6-benzoxazolyl 1 H 747. 2-quinazolinyl6-benzoxazolyl1 H 748. 3-(phenoxy)-6-pyridyl 1 H 749. 4-(phenylcarbonyl)phenyl 1 H750. 4-(phenylamino)phenyl 1 H 751. cyclohexyloxyphenyl 1 H 752.4-(3-thienyl)phenyl 1 H 753. 4-(pyrazol-3-yl)phenyl 1 H 754.4-chlorophenyl 1 EtO₂CCH═CH— 755. 4-chlorophenyl 1 5-Br 756. 4-pyridyl 1H 757. 4-pyridyl 1 H 758. 4-chlorophenyl 1 6-F 759. 3,4-dichlorophenyl-1 6-CH₃ 760. 4-fluorophenyl 1 H 761. 3-chlorophenyl 1 H 762.3-fluorophenyl 1 H 763. 3-fluoro-4-methoxyphenyl 1 H 764.3-fluoro-4-methylphenyl 1 H 765. 4-phenoxyphenyl 1 H 766.3-phenoxyphenyl 1 H 767. 4-biphenyl 1 H 768. 4-cyclohexylphenyl 1 H 769.2-quinolyl 1 H 770. 3-isoquinolyl 1 H 771. 3-quinolyl 1 H 772.1-isoquinolyl 1 H 773. 5-quinolyl 1 H 774. 5-isoquinolyl 1 H 775.6-quinolyl 1 H 776. 6-isoquinolyl 1 H 777. 7-quinolyl 1 H 778.7-isoquinolyl 1 H 779. 4-quinolyl 1 H 780. 4-isoquinolyl 1 H 781.4-pyridyl 1 H 782. 4-pyrimidinyl 1 H 783. 2-pyrimidinyl 1 H 784.6-pyrimidinyl 1 H 785. 4-pyridazinyl 1 H 786. 5-pyridazinyl 1 H 787.4-indolyl 1 H 788. 5-isoindolyl 1 H 789. 5-naphthyridinyl 1 H 790.6-quinozalinyl 1 H 791. 6-isoquinolyl 1 H 792. 4-naphthyridinyl 1 H 793.5-quinozalinyl 1 H 794. 4-naphthyridinyl 1 H 795. 7-tetrahydroquinolinyl1 H 796. 6-indazolyl 1 H 797. 6-isoindolyl 1 H 798. 5-indazolyl 1 H 799.5-isoindolyl 1 H 800. 6-benzothienyl 1 H 801. 6-benzofuryl 1 H 802.5-benzothienyl 1 H 803. 5-benzofuryl 1 H 804. 2-benzimidazolyl 1 H 805.2-benzoxazolyl 1 H 806. 2-benzthiazolyl 1 H 807. 6-benzimidazolyl 1 H808. 6-benzoxazolyl 1 H 809. 6-benzthiazolyl 1 H 810. 2-quinazolinyl 1 H811. 3-(phenoxy)-6-pyridyl 1 H 812. 4-(phenylcarbonyl)phenyl 1 H 813.4-(phenylamino)phenyl 1 H 814. 4-cyclohexyloxyphenyl 1 H 815.4-(3-thienyl)phenyl 1 H 816. 4-(pyrazol-3-yl)phenyl 1 H 817.3,4-dichlorophenyl 1 H

TABLE 9

# R¹ on R² 818. 4-chlorophenyl 1 6-F 819. 3-fluoro-4-methoxyphenyl 1 H820. 4-phenoxyphenyl 1 H 821. 4-biphenyl 1 H 822. 4-cyclohexylphenyl 1 H823. 2-quinolyl 1 H 824. 3-isoquinolyl 1 H 825. 3-quinolyl 1 H

Example 826

N-[4-(tert-Butyl)phenyl]{2-[(2,3-dihydrobenzo[b]furan-5-ylmethyl)amino](3-pyridyl)}carboxamide

The titled compound was prepared from2,3-dihydrobenzo[b]furan-5-ylmethylamine by the method described inExample 25. MS: (ES+) 402 (M+1)⁺; (ES−): 400 (M−1)⁻. Calc'd. forC₂₅H₂₇N₃O₂: 401.21.

Example 827

{2-[(2,3-Dihydrobenzo[b]furan-5-ylmethyl)amino](3-pyridyl)}-N-[3-(trifluoromethyl)phenyl]carboxamide

The titled compound was prepared from2,3-dihydrobenzo[b]furan-5-ylmethylamine by the method described inExample 25. MS: (ES+) 414 (M+1)⁺; (ES−): 412 (M−1)⁻. Calc'd. forC₂₂H₁₈F₃N₃O₂: 413.14.

The following compounds (Examples 828-864) were synthesized by themethod described in Example 25 or Example 82 unless specificallydescribed.

TABLE 10

# Y R¹ M + H calc'd 828. —NH(CH₂)₂—

375 374.2 829. —NH(CH₂)₂—

375 374.2 830. —NH(CH₂)₂—

411 410.2 831. —NH(CH₂)₂—

387 386.1 832. —NH(CH₂)₂—

361 360.2 833. —NH(CH₂)₂—

457 456.6 834. —NH(CH₂)₂—

437 436.4 835. —NH(CH₂)₂—

485.3 484.7 836. —NH(CH₂)₂—

388.3 387.5 837. —NH(CH₂)₂—

485.3 484.6 838. —NH(CH₂)₂—

486 485.5 839. —NH(CH₂)₂—

586.4 585.6 840. —NH(CH₂)₂—

564 563.6 841. —NH(CH₂)₂—

580 579.6 842. —NH(CH₂)₂—

564 563.6 843. —NH(CH₂)₂—

499.2 498.7 844. —NH(CH₂)₂—

512.1 511.6 845. —NH(CH₂)₂—

497.6 846. —NHCH₂—CH(4-morpholino)

521.5 847. —NH(CH₂)₂—

514 513.6 848. —NH(CH₂)₂—

548.6 849. —NH(CH₂)₂—

484.1 483.2 850. —NH(CH₂)₂—

438 437 851. —NH(CH₂)₂—

430.2 429.5 852. —NH(CH₂)₂—

429 428.6 853. —NH(CH₂)₂—

498.5 854. —NH(CH₂)₂—

599 598.6 855. —NH(CH₂)₂—

471.3 470.7 856. —NH(CH₂)₂—

458 457.3 857. —NH(CH₂)₂—

418.1 417.2 858. —NH(CH₂)₂—

402 401.1 859. —NH(CH₂)₂—

445.9 445.5 860. —NH(CH₂)₂—

432.1 431.5 861. —NH(CH₂)₂—

472.0 471.2 862. —NH(CH₂)₂—

416.3 415.2 863. —NH(CH₂)₂—

403.1 402.1 864. —NH(CH₂)₂—

472.1 471.2

Example 865

2-{[2-(1-Isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide

A solution of 2-fluoro-N-(4-trifluoromethyl-phenyl)-nicotinamide (107mg) and [2-(1-isopropyl-azetidin-3-ylmethoxy)-pyridin-4-yl]-methylamine(89 mg) and NaHCO₃ (95 mg) was dissolved in IpOH (10 ml) and heated to80° C. for 18 h. After cooling to RT, the mixture was diluted with EtOAc(50 ml) forming a precipitate which was filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (20% (12 N NH₃/MeOH)/EtOAc) to give the product as alight yellow oil. M+H 500.1; Calc'd 499.2.

The following compounds (Example 866-939) were synthesized by the methoddescribed above.

-   866)    N-(4-tert-Butyl-phenyl)-2-{[2-(1-isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 488.1; Calc'd —487.3-   867)    2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide.    M+H 485.3; Calc'd 484.6.-   868)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-nicotinamide.    M+H 457.1; Calc'd 456.5.-   869)    2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide.    M+H 612.6; Calc'd 611.8.-   870)    2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-1-(1-methylpiperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-nicotinamide.    M+H 526.3; Calc'd 525.7.-   871)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide.    M+H Calc'd 556.-   872)    2-({2-[2-(1-Methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide.    M+H Calc'd 513.-   873)    N-(4-tert-Butyl-phenyl)-2-{[2-ethylpyridin-4-ylmethyl]-amino}-nicotinamide.-   874)    N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide.    M+H Calc'd 487.-   875)    2-({2-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide.    M+H Calc'd 549.-   876)    N-(4-Pentafluoroethyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H Calc'd 535.-   877)    N-(4-tert-Butyl-phenyl)-2-{[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H Calc'd 473.-   878)    N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 571.4; Calc'd 570.3.-   879)    N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H Calc'd 584.-   880)    N-[3-(4-Boc-piperazine-1-carbonyl)-5-trifluoromethyl-phenyl]-2-(2-pyridin-4-yl-ethylamino)-nicotinamide.    M+H Calc'd 598.-   881)    N-[3-(4-Methyl-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H Calc'd 534.-   882)    N-[3-(4-Boc-piperazin-1-ylmethyl)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 621.4; Calc'd 620.-   883)    2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide.-   884)    N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.-   885)    2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-pentafluoroethyl-phenyl)-nicotinamide.    M+H 578.3. Calc'd 577.2.-   886)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.-   887)    N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 501.2; Calc'd 500.3.-   888)    N-(1-Boc-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.-   889)    N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 601.6; Calc'd 600.34.-   890)    N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.-   891)    N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.-   892)    N-[1-(2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.-   893)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide-   894)    N-[3,3-Dimethyl-1-(1-Boc-pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.-   895)    N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.-   896)    N-[3,3-Dimethyl-1-(2-Boc-amino-acetyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.-   897)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.    M+H 516.1.-   898)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.    M+H 501.3.-   899)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(4-Boc-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide.-   900)    2-{[2-(3-Morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.    M+H 566.-   901)    (S)2-{[2-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.    M+H 536.-   902)    N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 495. Calc'd 494.-   903)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 558; Calc'd 557.-   904)    N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 504. Calc'd 503.-   905)    N-(4-tert-Butyl-phenyl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 409; Calc'd 489.-   906)    2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide.    M+H 502; Calc'd 501.-   907)    2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide.    M+H 502; Calc'd 501.-   908)    2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.    M+H 552; Calc'd 551.-   909)    N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 481; Calc'd 480.-   910)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 545; Calc'd 544.-   911)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.-   912)    2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-trifluoromethyl-phenyl)-nicotinamide.-   913)    2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.-   914)    2-{[2-(1-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide.-   915)(R)N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 474; Calc'd 473.-   916)    (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.-   917)    (R)N-[3-(1-Methyl-pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 486; Calc'd 485.5.-   918)    N-[3-(1-Methyl-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.-   919)    N-[3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.-   920)    N-[4-tert-Butyl-3-(1-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 560; Calc'd 559.-   921)    N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.-   922)    2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-trifluoromethyl-phenyl)-nicotinamide.-   923)    2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide.-   924)    2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4-tert-butyl-phenyl)-nicotinamide.-   925)    2-({2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(3-tert-butyl-isoxazol-5-yl)-nicotinamide.-   926)    N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide.-   927)    2-[(Pyridin-4-ylmethyl)-amino]-N-(3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluoren-6-yl)-nicotinamide.-   928)    N-[3,3-Dimethyl-1-(1-Boc-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide-   929)    N-[3,3-Dimethyl-1-(1-methyl-piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 485.3; Calc'd 484.6.

The following compounds (Example 930-937) were synthesized by the methoddescribed above, substituting K₂CO₃ for NaHCO₃.

-   930)    2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.    M+H 550.2; Calc'd 549.2.-   932)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 543.4; Calc'd 542.3.-   933)    N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide.    M+H 504.3; Calc'd 503.6.-   934)    2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.    M+H 566.3; Calc'd 565.55.-   935)    2-{[2-(3-Morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide.    M+H 516.0; Calc'd 515.5.-   936)    N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.    M+H Calc'd 487.6.-   937)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.    M+H Calc'd 542.69.

The following compounds (Example 938-939) were synthesized by the methoddescribed above, substituting Cs₂CO₃ for NaHCO₃.

-   938)    2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-[3-(1-methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide.    M H 597.0; Calc'd 596.7.-   939)    N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 479; Calc'd 478.3.

The following compounds (Example 940-945) were synthesized by the methoddescribed above, substituting t-BuOH for IpOH.

-   940)    N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 558.1. Calc'd 557.6.-   941)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide.    M+H 588.1. Calc'd 587.2.-   942)    2-[(Pyridin-4-ylmethyl)-amino]-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-nicotinamide.    M+H 404.5; Calc'd 403.2.-   943)    N-(4-Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 432.1; Calc'd 431.5.-   944)    N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 404.5; Calc'd 403.2.-   945)    2-{[2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide.    M+H 598.4; Calc'd 597.3.

The following compounds (Example 946-993) were synthesized by the methoddescribed above, unless specifically described.

-   946)    N-(4,4-Dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with MeOH as the solvent at 110° C. M+H 402.3.-   947)    N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide    was prepared with pentanol at 95° C. M+H Calc'd 501.-   948)    N-(3-tert-Butyl-isoxazol-5-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide    was prepared with pyridine at 95° C. M+H Calc'd 492.-   949)    N-(3-trifluoromethylphenyl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide    was prepared with pyridine at 95° C. M+H Calc'd 513.-   950)    2-[(2,3-Dihydro-benzofuran-6-ylmethyl)-amino]-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide    was prepared with DIEA at 120° C. M+H 663.4; Calc'd 662.6.-   951)    (R)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with IpOH as the solvent at 135° C. M+H 566.5; Calc'd    565.5.-   952)    (S)N-[3-(2-Hydroxy-3-pyrrolidin-1-yl-propoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with IpOH as the solvent at 135° C. M+H 566.5; Calc'd    565.5.-   953)    N-[4-tert-Butyl-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with IpOH as the solvent at 130° C. M+H 488.3; Calc'd    487.6.-   954)    N-[3-(1-Methyl-piperidin-4-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with IpOH as the solvent at 135° C. M+H 550.2; Calc'd    549.5.-   955)    N-[4-Pentafluoroethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with IpOH as the solvent at 130° C. M+H 550.1; Calc'd    549.5.-   956)    N-[4-Trifluoromethyl-3-(2-piperidin-1-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with IpOH as the solvent at 130° C. M+H 486.3; Calc'd    485.5.-   957)    (S)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with DIEA at 135° C. M+H 572. Calc'd 571.6.-   958)    (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with DIEA at 130° C. M+H 622. Calc'd 621.6.-   959)    (R)N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with DIEA at 130° C. M+H 622.4. Calc'd 621.6.-   960)    N-(4-tert-Butyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide    was prepared with pyridine and TEA at 90° C.M+H 474.-   961)    N-(3-Trifluoromethyl-phenyl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide    was prepared with pyridine and TEA at 90° C. M+H 486.-   962)    N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide    was prepared with pyridine and TEA at 90° C. M+H 465.-   963)    N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with pyridine at 90° C. M+H 498; Calc'd 497.6.-   964)    N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared at 130° C. neat. M+H 500. Calc'd 499.2.-   965)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(1-Boc-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-nicotinamide    was prepared at 130° C. neat. M+H 602. Calc'd for C₃₀H₃₄F₃N₅O₅:    601.6.-   967)    N-{4-tert-Butyl-3-[2-(1-Boc-piperidin-4-yl)-ethoxy]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with DIEA and IpOH at 130° C. M+H 574.6.-   968)    N-[4-tert-Butyl-3-(1-methyl-azetidin-3-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with IpOH and DIEA at 130° C. M+H 546.-   969)    N-(3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared neat at 130° C. M+H 424; Calc'd 423.-   970)    N-[1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphth-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared neat at 130° C. M+H 415; Calc'd 414.-   971)    N-{4-[1-Methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with pyridine. M+H 444; Calc'd 443.27.-   972)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-{4-[1-methyl-1-(1-methyl-piperidin-4-yl)-ethyl]-phenyl}-nicotinamide    was prepared with pyridine and NaHCO₃ at 110° C. MS: 473 (M+H),    Calc'd for C₂₈H₃₅N₅O₂—472.6.-   973)    N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with IpOH at 120° C. M+H 375. Calc'd for C₂₇H₃₂N₆O:    374.-   974)    2-{[2-(3-Dimethylamino-propoxy)-pyridin-4-ylmethyl]-amino}-N-(4-pentafluoroethyl-phenyl)-nicotinamide.    M+H 524; Calc'd 523.2.-   975)    N-[3-(1-Methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 470.4; Calc'd 469.21.-   976)    2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-[3-(1-methyl-piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide.    M+H 597.0; Calc'd 596.31.-   977)    N-[3-(azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 458.1; Calc'd 457.2.-   978)    N-(3-Hydroxy-5-trifluoromethyl-phenyl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 388.9; Calc'd 388.11.-   979)    N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 430; Calc'd 429.22.-   980)    N-[2-(4-methoxy-benzyl)-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 522.3; Calc'd 521.24.-   981)    N-(2-Acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(quinolin-4-ylmethyl)-amino]-benzamide.    M+H 479; Calc'd 478.24.-   982)    2-[(Pyridin-4-ylmethyl)-amino]-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide.    M+H 486; Calc'd 485.-   983)    2-{[2-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-nicotinamide.    M+H 500.5; Calc'd 499.5.-   984)    N-[3-(1-Boc-azetidin-3-ylmethoxy)-4-tert-butyl-phenyl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 546. Calc'd 545.-   985)    2-Methyl-2-[4-({2-[(pyridin-4-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-phenyl]-propionic    acid methyl ester. M+H 405; Calc'd 404.-   986)    N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide.    M+H 504.3; Calc'd 503.-   987)    N-(4-pentafluoroethyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide.    M+H 566.3; Calc'd 565.-   988)    N-(4-trifluoromethyl-phenyl)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]-amino}-nicotinamide.    M+H 516.0; Calc'd 515.-   989)    N-(4-tert-Butyl-phenyl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.    M+H 488.4; Calc'd 487.-   990)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.    M+H 543.5; Calc'd 542.-   991)    N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-nicotinamide.    M+H 459.3.-   992)    2-({2-[2-(1-Methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-N-(3-trifluoromethyl-phenyl)-nicotinamide.    M+H 500.4; Calc'd 499.

Example 993

N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide

N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-piperidin-4-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide(300 mg, Example 871) was dissolved in conc. HCl (20 ml) and EtOH (20ML) and heated at 70° C. for 4 H. The mixture was concentrated and theresidue was diluted with sat'd NaHCO₃ and CH₂Cl₂. The organic layer wasdried over Na₂SO₄ and concentrated to obtain the desired compound. M+H515. Calc'd for C₃₀H₃₈N₆O₂: 514.

The following compounds (Example 995-1009) were synthesized by themethod described above, unless specifically described.

-   995)    N-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 390.3; Calc'd 389.4.-   996)    N-(4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 388.3.-   997)    N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 501.3; Calc'd 500.3.-   998)    N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with 1N HCl in ether and dioxane at RT. M+H 457.2;    Calc'd 456.7.-   999)    N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.    M+H Calc'd 500.65.-   1000)    N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 404.3; Calc'd 403.2.-   1001)    N-[3,3-Dimethyl-1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with HCl in EtOAc. M+H 501.4; Calc'd 500.3.-   1002)    N-(3,3-Dimethyl-1-piperidin-4-yl-2,3-dihydro-1H-indol-6-yl)-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 487.4; Calc'd 486.3.-   1003)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperidin-4-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide    was prepared with HCl in EtOAc.-   1004)    N-[3,3-Dimethyl-1-(pyrrolidin-2-ylmethyl)-2,3-dihydro-1H-indol-6-yl]-2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide    was prepared with HCl in EtOAc.-   1005)    2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-nicotinamide    was prepared with HCl in EtOAc. M+H 501.3.-   1006)    N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 503; Calc'd 502.-   1007)    N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(1-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 529.-   1008)    N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propylamino)-pyridin-4-ylmethyl]-amino}-nicotinamide.    M+H 516; Calc'd 515.-   1009)    N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-({2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide.    M+H 501.4; Calc'd 500.

Example 1010

N-(4-Pentafluoroethyl-phenyl)-2-[(pyrimidin-4-ylmethyl)-amino]-nicotinamide

2-Amino-N-(4-pentafluoroethyl-phenyl)-nicotinamide (180 mg), TsOH (40mg) and a solution of pyrimidine-4-carboxaldehyde in DMSO (10 ml) werestirred at 60 C for 6 h. Treated with NaBH₄ (200 mg) and stirred for 2 hat RT. MS (ES⁺): 566.3 (M+H)⁺; Calc'd for C₂₆H₂₈F₅N₇O₂—565.

Example 1011

2-{[2-(Azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)nicotinamide

2-{[2-(1-Benzhydryl-azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl-phenyl)-nicotinamide(210 mg) was heated at reflux with Et₃SiH (5 ml) and TFA (15 ml) for 9h. The mixture was concentrated, then diluted with CH₂Cl₂ (50 ml) andwashed with sat'd NaHCO₃ (50 ml) and brine (30 ml), dried over MgSO₄ andpurified by silica gel chromatography (10% MeOH/2M NH₃ 90% EtOAc) toafford the product as a yellow solid. M+H Calc'd for C₂₅H₂₉N₅O₂: 431.2.

Example 1012

N-(2,3,3-Trimethyl-1,1-dioxo-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-benzamide

N-(3,3-Dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-benzamide(110 mg) was dissolved in DMF and added NaH (30 mg). The mix was stirredfor 15 min then MeI (18 ul) was added and stirred for 10 min. TheSolvent was evaporated and purified by preparative TLC (10% MeOH/EtOAc)to give the product. M+H 438; Calc'd for C₂₂H₂₃N₅O₃S: 437.1.

The following compounds (Example 1013-1014) were synthesized by themethod described above, unless specifically described.

-   1013)    N-[3,3-Dimethyl-1,1-dioxo-2-(2-piperidin-1-yl-ethyl)-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 535; Calc'd for C₂₈H₃₄N₆O₃S: 534.-   1014)    N-[2-(2-Dimethylamino-ethyl)-3,3-dimethyl-1,1-dioxo-2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide.    M+H 495; Calc'd 494.

Example 1015

-   2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-(1-Boc-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide

M+H 529.4. Calc'd for 528.3.

Example 1016

2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-(4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-nicotinamide

M+H 429.2. Calc'd for 228.2.

Example 1017

2-[(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[4-pentafluoroethyl-3-(pyrrolidin-2-ylmethoxy)-phenyl]-nicotinamide

M+H 663.4. Calc'd for 662.3.

Example 1018

N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-nicotinamide

M+H 381.3. Calc'd for .

Example 1019

N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-nicotinamide

M+H 430. Calc'd for .

Example 1020

N-(4-Pentafluoroethyl-phenyl)-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-nicotinamide

M+H 432.2. Calc'd for .

Although the pharmacological properties of the compounds of FormulaI-XII vary with structural change, in general, activity possessed bycompounds of Formula I-XII may be demonstrated in vivo. Thepharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological in vitro assays. Theexemplified pharmacological assays which follow have been carried outwith the compounds according to the invention and their salts. Compoundsof the present invention showed inhibition of KDR kinase at doses lessthan 50 μM.

Biological Evaluation HUVEC Proliferation Assay

Human Umbilical Vein Endothelial cells are purchased from Clonetics,Inc., as cryopreserved cells harvested from a pool of donors. Thesecells, at passage 1, are thawed and expanded in EBM-2 complete medium,until passage 2 or 3. The cells are trypsinized, washed in DMEM+10%FBS+antibiotics, and spun at 1000 rpm for 10 min. Prior tocentrifugation of the cells, a small amount is collected for a cellcount. After centrifugation, the medium is discarded, and the cells areresuspended in the appropriate volume of DMEM+10% FBS+antibiotics toachieve a concentration of 3×10⁵ cells/mL. Another cell count isperformed to confirm the cell concentration. The cells are diluted to3×10⁴ cells/mL in DMEM+10% FBS+antibiotics, and 100 μL of cells areadded to a 96-well plate. The cells are incubated at 37° C. for 22 h.

Prior to the completion of the incubation period, compound dilutions areprepared. Five-point, five-fold serial dilutions are prepared in DMSO,at concentrations 400-fold greater than the final concentrationsdesired. 2.5 μL of each compound dilution are diluted further in a totalof 1 mL DMEM+10% FBS+antibiotics (400× dilution). Medium containing0.25% DMSO is also prepared for the 0 μM compound sample. At the 22-hourtimepoint, the medium is removed from the cells, and 100 μL of eachcompound dilution is added. The cells are incubated at 37° C. for 2-3 h.

During the compound pre-incubation period, the growth factors arediluted to the appropriate concentrations. Solutions of DMEM+10%FBS+antibiotics, containing either VEGF or bFGF at the followingconcentrations: 50, 10, 2, 0.4, 0.08, and 0 ng/mL are prepared. For thecompound-treated cells, solutions of VEGF at 550 ng/mL or bFGF at 220ng/mL for 50 ng/mL or 20 ng/mL final concentrations, respectively, areprepared since 10 μL of each will be added to the cells (110 μL finalvolume). At the appropriate time after adding the compounds, the growthfactors are added. VEGF is added to one set of plates, while bFGF isadded to another set of plates. For the growth factor control curves,the media on wells B4-G6 of plates 1 and 2 are replaced with mediacontaining VEGF or bFGF at the varying concentrations (50-0 ng/mL). Thecells are incubated at 37° C. for an additional 72 h.

At the completion of the 72 h incubation period, the medium is removed,and the cells are washed twice with PBS. After the second wash with PBS,the plates are tapped gently to remove excess PBS, and the cells areplaced at −70° C. for at least 30 min. The cells are thawed and analyzedusing the CyQuant fluorescent dye (Molecular Probes C-7026), followingthe manufacturer's recommendations. The plates are read on aVictor/Wallac 1420 workstation at 485 nm/530 nm (excitation/emission).Raw data are collected and analyzed using a 4-parameter fit equation inXLFit. IC₅₀ values are then determined.

Examples 4, 7, 20-21, 25-26, 28, 33, 67, 72(f-i, n-o), 78, 82, 84, 86,94-95, 97-100, 105, 111-112, 115-118, 130, 133, 138, 140, 151, 154-156,158-159, 165, 167, 169, 817, 826-829, 831-838, 840-844, 845, 847-851,853, 855-860, 862, 864, 873, 900, 904-905, 916-917, 922-924, 942-944,946, 951-952, 954-955, 963-964, 973, 977-978, 982, 985, 991, 995, 1000and 1008 inhibited VEGF-stimulated HUVEC proliferation at a level below50 nm.

Angiogenesis Model

To determine the effects of the present compounds on angiogenesis invivo, selective compounds are tested in the rat cornealneovascularization micropocket model or the angiogenesis assay ofPassaniti, Lab. Invest., 67, 519-28 (1992).

Rat Corneal Neovascularization Micropocket Model

In Life Aspects:

Female Sprague Dawley rats weighing approximately 250 g were randomizedinto one of five treatment groups. Pretreatment with the vehicle orcompound was administered orally, 24 h prior to surgery and continuedonce a day for seven additional days. On the day of surgery, the ratswere temporarily anesthetized in an Isofluorane gas chamber (delivering2.5 liters/min oxygen+5% Isofluorane). An othoscope was then placedinside the mouth of the animal to visualize the vocal cords. Atip-blunted wire was advanced in between the vocal cords and used as aguide for the placement of an endotracheal Teflon tube (Small Parts Inc.TFE-standard Wall R-SWTT-18). A volume-controlled ventilator (HarvardApparatus, Inc. Model 683) was connected to the endotracheal tube todeliver a mixture of oxygen and 3% Isofluorane. Upon achieving deepanesthesia, the whiskers were cut short and the eye areas and eyesgently washed with Betadine soap and rinsed with sterile saline. Thecorneas were irrigated with one to two drops of Proparacaine HClophthalmic topical anesthetic solution (0.5%) (Bausch and LombPharmaceuticals, Tampa Fla.). The rat was then positioned under thedissecting microscope and the corneal surface brought into focus. Avertical incision was made on the midline of the cornea using a diamondblade knife. A pocket was created by using fine scissors to separate theconnective tissue layers of the stroma, tunneling towards the limbus ofthe eye. The distance between the apex of the pocket and the limbus wasapproximately 1.5 mm. After the pocket had been made, the soakednitrocellulose disk filter (Gelman Sciences, Ann Arbor Mich.) wasinserted under the lip of the pocket. This surgical procedure wasperformed on both eyes. rHu-bFGF soaked disks were placed into the righteye, and the rHu-VEGF soaked disks were placed into the left eye.Vehicle soaked disks were placed in both eyes. The disk was pushed intoposition at the desired distance from the limbal vessels. Ophthalmicantibiotic ointment was applied to the eye to prevent drying andinfection. After seven days, the rats were euthanized by CO₂asphyxiation, and the eyes enucleated. The retinal hemisphere of the eyewas windowed to facilitate fixation, and the eye placed into formalinovernight.

Post Mortem Aspects:

After twenty-four hours in fixative, the corneal region of interest wasdissected out from the eye, using fine forceps and a razorblade. Theretinal hemisphere was trimmed off and the lens extracted and discarded.The corneal dome was bisected and the superfluous cornea trimmed off.The iris, conjunctiva and associated limbal glands were then carefullyteased away. Final cuts were made to generate a square 3×3 mm containingthe disk, the limbus, and the entire zone of neovascularization.

Gross Image Recording:

The corneal specimens were digitally photographed using a Sony CatsEyeDKC5000 camera (A. G. Heinz, Irvine Calif.) mounted on a Nikon SMZ-Ustereo microscope (A. G. Heinz). The corneas were submerged in distilledwater and photographed via trans-illumination at approximately 5.0diameters magnification.

Image Analysis:

Numerical endpoints were generated using digital micrographs collectedfrom the whole mount corneas after trimming and were used for imageanalysis on the Metamorph image analysis system (Universal ImagingCorporation, West Chester Pa.). Three measurements were taken: Diskplacement distance from the limbus, number of vessels intersecting a 2.0mm perpendicular line at the midpoint of the disk placement distance,and percent blood vessel area of the diffusion determined bythresholding.

General Formulations:

0.1% BSA in PBS Vehicle:

0.025 g of BSA was added to 25.0 ml of sterile 1× phosphate bufferedsaline, gently shaken until fully dissolved, and filtered at 0.2 μm.Individual 1.0 ml samples were aliquoted into 25 single use vials, andstored at −20° C. until use. For the rHu-bFGF disks, a vial of this 0.1%BSA solution was allowed to thaw at room temperature. Once thawed, 10 μlof a 100 mM stock solution of DTT was added to the 1 ml BSA vial toyield a final concentration of 1 mM DTT in 0.1% BSA.

rHu-VEGF Dilutions:

Prior to the disk implant surgery, 23.8 μl of the 0.1% BSA vehicle abovewas added to a 10 μg rHu-VEGF lyophilized vial yielding a finalconcentration of 10 μM.

rHu-bFGF: Stock concentration of 180 ng/μl:

R&D rHu-bFGF: Added 139 μl of the appropriate vehicle above to the 25 μgvial lyophilized vial. 13.3 μl of the [180 ng/μl] stock vial and added26.6 μl of vehicle to yield a final concentration of 3.75 μMconcentration.

Nitro-Cellulose Disk Preparation:

The tip of a 20-gauge needle was cut off square and beveled with emerypaper to create a punch. This tip was then used to cut out ≅0.5 mmdiameter disks from a nitrocellulose filter paper sheet (GelmanSciences). Prepared disks were then placed into Eppendorf microfugetubes containing solutions of either 0.1% BSA in PBS vehicle, 10 μMrHu-VEGF (R&D Systems, Minneapolis, Minn.), or 3.75 μM rHu-bFGF (R&DSystems, Minneapolis, Minn.) and allowed to soak for 45-60 min beforeuse. Each nitrocellulose filter disk absorbs approximately 0.1 μl ofsolution.

In the rat micropocket assay, compounds of the present invention willinhibit angiogenesis at a dose of less than 50 mg/kg/day.

Tumor Model

A431 cells (ATCC) are expanded in culture, harvested and injectedsubcutaneously into 5-8 week old female nude mice (CD1 nu/nu, CharlesRiver Labs) (n=5-15). Subsequent administration of compound by oralgavage (10-200 mpk/dose) begins anywhere from day 0 to day 29 post tumorcell challenge and generally continues either once or twice a day forthe duration of the experiment. Progression of tumor growth is followedby three dimensional caliper measurements and recorded as a function oftime. Initial statistical analysis is done by repeated measures analysisof variance (RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control.Compounds of the present invention are active at doses less than 150mpk.

Rat Adjuvant Arthritis Model

The rat adjuvant arthritis model (Pearson, Proc. Soc. Exp. Biol. 91,95-101 (1956)) is used to test the anti-arthritic activity of compoundsof the formula I, or salts thereof. Adjuvant Arthritis can be treatedusing two different dosing schedules: either (i) starting time ofimmunization with adjuvant (prophylactic dosing); or from day 15 whenthe arthritic response is already established (therapeutic dosing).Preferably a therapeutic dosing schedule is used.

Rat Carrageenan-induced Analgesia Test

The rat carrageenan analgesia test was performed with materials,reagents and procedures essentially as described by Hargreaves, et al.,(Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated aspreviously described for the Carrageenan Foot Pad Edema test. Threehours after the injection of the carrageenan, the rats were placed in aspecial plexiglass container with a transparent floor having a highintensity lamp as a radiant heat source, positionable under the floor.After an initial twenty minute period, thermal stimulation was begun oneither the injected foot or on the contralateral uninjected foot. Aphotoelectric cell turned off the lamp and timer when light wasinterrupted by paw withdrawal. The time until the rat withdraws its footwas then measured. The withdrawal latency in seconds was determined forthe control and drug-treated groups, and percent inhibition of thehyperalgesic foot withdrawal determined.

Formulations

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I in associationwith one or more non-toxic, pharmaceutically-acceptable carriers and/ordiluents and/or adjuvants (collectively referred to herein as “carrier”materials) and, if desired, other active ingredients. The activecompounds of the present invention may be administered by any suitableroute, preferably in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended. Thecompounds and compositions of the present invention may, for example, beadministered orally, mucosally, topically, rectally, pulmonarily such asby inhalation spray, or parentally including intravascularly,intravenously, intraperitoneally, subcutaneously, intramuscularlyintrasternally and infusion techniques, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers, adjuvants,and vehicles.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,preferably from about 1 to 500 mg or 5 to 1000 mg. A suitable daily dosefor a human or other mammal may vary widely depending on the conditionof the patient and other factors, but, once again, can be determinedusing routine methods.

The amount of compounds which are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, preferably between about 0.1 and about50 mg/kg, and more preferably about 0.1 and about 20 mg/kg body weightmay be appropriate. The daily dose can be administered in one to fourdoses per day.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include dimethylsulfoxide and relatedanalogs.

The compounds of this invention can also be administered by atransdermal device. Preferably transdermal administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The active ingredients are preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%and particularly about 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles solvents that may be employed are water, Ringer'ssolution, and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed, includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

All mentioned references, patents, applications and publications, arehereby incorporated by reference in their entirety, as if here written.

What is claimed is:
 1. A method of treating angiogenesis in a subject,said method comprising administering an effective amount of a compoundas in any of Formula XI

wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused heteroaryl, where substituted R issubstituted with one or more substituents selected from halo, amino,hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; wherein R¹ is aring selected from unsubstituted or substituted 4-6 membered saturatedor partially un-saturated monocyclic heterocyclyl, 9-10 memberedsaturated or partially un-saturated bicyclic heterocyclyl, and 13-14membered saturated or partially un-saturated tricyclic heterocyclyl,wherein substituted R¹ is substituted with one or more substituentsselected from halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substituted 4-6membered heterocyclyl-C₁-C₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₂-C₄-alkenyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted phenyloxy, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, oxo, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl,halosulfonyl, C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R⁴ is selected from a direct bond,C₁₋₄-alkyl, and

wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; and wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₃-alkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; andpharmaceutically acceptable salts thereof.
 2. A method of treatingKDR-related disorders in a mammal, said method comprising administeringan effective amount of a compound of Formula XI

wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused heteroaryl, where substituted R issubstituted with one or more substituents selected from halo, amino,hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; wherein R¹ is aring selected from unsubstituted or substituted 4-6 membered saturatedor partially un-saturated monocyclic heterocyclyl, 9-10 memberedsaturated or partially un-saturated bicyclic heterocyclyl, and 13-14membered saturated or partially un-saturated tricyclic heterocyclyl,wherein substituted R¹ is substituted with one or more substituentsselected from halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substituted 4-6membered heterocyclyl-C₁-C₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₂-C₄-alkenyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted phenyloxy, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, oxo, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl,halosulfonyl, C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R⁴ is selected from a direct bond,C₁₋₄-alkyl, and

wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; and wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₃-alkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; andpharmaceutically acceptable salts thereof.
 3. A method of treatingproliferative disorders in a mammal, said method comprisingadministering an effective amount of a compound of Formula XI

wherein R is selected from a) unsubstituted or substituted 5- or6-membered nitrogen-containing heteroaryl, and b) unsubstituted orsubstituted 9- or 10-membered fused heteroaryl, where substituted R issubstituted with one or more substituents selected from halo, amino,hydroxy, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkoxy, optionally substitutedheterocyclyl-C₁₋₆-alkylamino, optionally substitutedheterocyclyl-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₂₋₄-alkynyl,C₁₋₆-alkylamino-C₁₋₆-alkoxy, C₁₋₆-alkylamino-C₁₋₆-alkoxy-C₁₋₆-alkoxy,and optionally substituted heterocyclyl-C₂₋₄-alkynyl; wherein R¹ is aring selected from unsubstituted or substituted 4-6 membered saturatedor partially un-saturated monocyclic heterocyclyl, 9-10 memberedsaturated or partially un-saturated bicyclic heterocyclyl, and 13-14membered saturated or partially un-saturated tricyclic heterocyclyl,wherein substituted R¹ is substituted with one or more substituentsselected from halo, C₁₋₆-alkyl, optionally substituted C₃₋₆-cycloalkyl,optionally substituted phenyl, optionally substitutedphenyl-C₁-C₄-alkylenyl, C₁₋₂-haloalkoxy, optionally substituted 4-6membered heterocyclyl-C₁-C₄-alkyl, optionally substituted 4-6 memberedheterocyclyl-C₂-C₄-alkenyl, optionally substituted 4-6 memberedheterocyclyl, optionally substituted phenyloxy, optionally substituted4-6 membered heterocyclyloxy, optionally substituted 4-6 memberedheterocyclyl-C₁-C₄-alkoxy, optionally substituted 4-6 memberedheterocyclylsulfonyl, optionally substituted 4-6 memberedheterocyclylamino, optionally substituted 4-6 memberedheterocyclylcarbonyl, optionally substituted 5-6 memberedheterocyclyl-C₁₋₄-alkylcarbonyl, C₁₋₂-haloalkyl, C₁₋₄-aminoalkyl, nitro,amino, hydroxy, oxo, cyano, aminosulfonyl, C₁₋₂-alkylsulfonyl,halosulfonyl, C₁₋₄-alkylcarbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkoxy, C₁₋₃-alkylamino-C₁₋₃-alkoxy-C₁₋₃-alkoxy,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl,C₁₋₄-hydroxyalkyl,

 and C₁₋₄-alkoxy; wherein R² is one or more substituents independentlyselected from H, halo, hydroxy, amino, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-alkoxy, C₁₋₂-alkylamino, aminosulfonyl, C₃₋₆-cycloalkyl, cyano,C₁₋₂-hydroxyalkyl, nitro, C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₁₋₆-haloalkoxy,C₁₋₆-carboxyalkyl, 5-6-membered heterocyclyl-C₁₋₆-alkylamino,unsubstituted or substituted phenyl and unsubstituted or substituted 5-6membered heterocyclyl; wherein R⁴ is selected from a direct bond,C₁₋₄-alkyl, and

wherein R^(z) is selected from C₁₋₂-alkyl, C₂₋₆-branched alkyl,C₂₋₄-branched haloalkyl, amino-C₁₋₄-alkyl andC₁₋₂-alkylamino-C₁₋₂-alkyl; wherein R^(e) and R^(f) are independentlyselected from H and C₁₋₂-haloalkyl; and wherein R⁷ is selected from H,C₁₋₃-alkyl, optionally substituted phenyl, optionally substitutedphenyl-C₁₋₃-alkyl, optionally substituted 4-6 membered heterocyclyl,optionally substituted 4-6 membered heterocyclyl-C₁-C₃-alkyl,C₁₋₃-alkoxy-C₁₋₂-alkyl and C₁₋₃-alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkyl; andpharmaceutically acceptable salts thereof.
 4. The method of claim 1wherein said compound is N-(3,3-dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide and pharmaceuticallyacceptable salts thereof.
 5. The method of claim 1 comprising acombination with a compound selected from antibiotic-type agents,alkylating agents, antimetabolite agents, hormonal agents, immunologicalagents, interferon-type agents and miscellaneous agents.